KR101120857B1 - 5-membered heterocycle-based p38 kinase inhibitors - Google Patents

Abstract

Provided are 5-membered heterocycle-based p38 kinase inhibitors. Further provided are pyrazole and imidazole-based p38 kinase, including p38± and p38² kinase, inhibitors. Pharmaceutical composititons coataining the compounds are also provided. Methods of use of the compounds and compositions are also provided, including methods of treatment, prevention, or amelioration of one or more symptoms of p38 Kinase mediated diseases and disorders, including, but not limited to, inflammatory diseases and disorders.

Description

5-MEMBERED HETEROCYCLE-BASED P38 KINASE INHIBITORS} 5-membered heterocycle-based ASE38 kinase inhibitor

The application provides five membered heterocycle-based compounds, including pyrazole- and imidazole-based compounds having cytokine inhibitory activity. Also provided are the use of compounds for the treatment of symptoms associated with p38α and β kinases and for the treatment of p38 kinase-related symptoms.

Many cytokines, including IL-1, IL6, IL-8 and TNF-α, participate in inflammatory responses. Overproduction of cytokines such as IL-1 and TNF-α can cause a variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure. (Henry et al., Drugs Fut ., 24: 1345-1354 (1999); Salituro et al., Curr . Med . Chem ., 6: 807-823 (1999)]. Evidence in human patients includes monoclonal antibodies to TNF-α (Remicade) (Rankin et al., Br. J. Rheumatol ., 34: 334-342 (1995)) and soluble TNF- Protein antagonists of cytokines such as α receptor-Fc fusion proteins (Etanercept) (Moreland et al., 25 Ann. Intern. Med ., 130: 478-486 (1999)) are chronic inflammatory diseases It is effective to treat.

Biosynthesis of TNF-α occurs in many cell types in response to external stimuli such as mitogen, infectious organisms or trauma. Important mediators of TNF-α production are mitogen-activated protein (MAP) kinases, and in particular p38 kinases. These kinases are activated in response to various stress stimuli, including but not limited to pro-inflammatory cytokines, endotoxins, ultraviolet light and osmotic shock. Activation of p38 requires double phosphorylation on threonine and tyrosine in the Thr-Gly-Tyr residue (motif) that is characteristic of the p38 isoenzyme by upstream MAP kinases (MKK3 and MKK6).

There are four known homologues of p38, namely p38α, p38β, p38γ and p38δ. α and β homologues are expressed in inflammatory cells and are the major mediators of TNF-α production. Inhibition of p38α and β enzymes in cells decreases TNF-α expression levels. In addition, administration of inhibitors of p38α and β in animal models of inflammatory diseases demonstrate that the inhibitors are effective in treating inflammatory diseases. Thus, the p38 enzyme plays an important role in the inflammatory process mediated by IL-1 and TNF-α. See, for example, US Pat. Nos. 6,277,989, 6,130,235, 6,147,080, 5,945,418, 6,251,914, 5,977,103, 5,658,903, 5,932,576 and 6,087,496; And International Patent Application Nos. WO 00/56738, WO 01/27089, WO 01/34605, WO 00/12497, WO 00/56738, WO 00/12497 and WO 00/12074. See also US Pat. No. 6,376,527; 6,316,466 and 6,444,696; And International Patent Application Nos. WO 99/57101, WO 02/40486, WO 03/032970, WO 03/033482, WO 03/032971, WO 03/032986, WO 03/032980, WO 03/032987, WO 03/033483, See WO 03/033457 and WO 03/032972.

As such, there is a need for inhibitors of p38 kinases including p38α and p38β kinases to treat, prevent or alleviate one or more symptoms of diseases and disorders associated with p38 kinase activity.

summary

The application provides compounds, compositions and methods for treating, preventing or alleviating one or more symptoms of diseases and disorders associated with p38 kinase activity. In one embodiment, the compounds used in the compositions and methods are pyrazole- or imidazole-based compounds. In another embodiment, the pyrazole- or imidazole-based compounds are useful as inhibitors of kinases, including p38α and p38β kinases.

In one embodiment, a compound provided herein comprises a compound of the formula: or a pharmaceutically acceptable derivative thereof.

R ¹ is hydrogen, acyl or —P (O) (OH) ₂ ;

R ² is hydrogen, halo, optionally substituted alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted alkoxy, optionally substituted heterocyclyloxy, or alkylamino;

G is a heterocyclyl ring optionally fused to an aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl, or phenyl ring, substituted with R ³ and R ⁴ , provided that the heterocyclyl ring is substituted via a carbon ring atom Attached to a carbonyl group, or G is OR ⁸³ or NR ⁸⁰ R ⁸¹ ;

B is an aryl or heteroaryl ring;

C is a 5 membered heteroaryl ring containing 1 or 2 heteroatoms in the ring;

D is heteroaryl, optionally substituted heteroaryl, or -C (O) NR ⁸⁰ R ⁸¹ ;

Each R ⁸⁰ and R ⁸¹ is independently hydrogen, alkyl, optionally substituted cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl or they together form an optionally substituted alkylene or heteroalkylene;

R ⁸³ is hydrogen, alkyl, cycloalkyl, heteroaryl or optionally substituted heteroaryl;

R ³ is

(a) amino, alkylamino or dialkylamino;

(b) acylamino;

(c) optionally substituted heterocyclyl;

(d) optionally substituted aryl or heteroaryl;

(e) heteroalkyl;

(f) heteroalkenyl;

(g) heteroalkynyl;

(h) heteroalkoxy;

(i) heteroalkylamino;

(j) optionally substituted heterocyclylalkyl;

(k) optionally substituted heterocyclylalkenyl;

(l) optionally substituted heterocyclylalkynyl;

(m) optionally substituted heterocyclylarylalkoxy or heterocyclyloxy;

(n) optionally substituted heterocyclylalkylamino;

(o) optionally substituted heterocyclylalkylcarbonyl;

(p) heteroalkylcarbonyl;

(q) -NHSO ₂ R ⁶ , wherein R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;

(r) -NHSO ₂ NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently of each other hydrogen, alkyl or heteroalkyl;

(s) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O-, -NH- or -S (O) _n -wherein n is an integer from 0 to 2; R ⁹ is halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -COOH, -COR ¹⁰ , -COOR ¹¹ , -CONR ¹² R ¹³ , -SO ₂ R ¹⁴ ,- SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ¹⁷ or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹⁰ is alkyl or optionally substituted heterocycle, R ¹¹ is alkyl, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl);

(t) -C (= NR ²⁰ ) (NR ²¹ R ²² ), where R ²⁰ , R ²¹ And R ²² independently represents hydrogen, alkyl or hydroxy, or R ²⁰ And R ²¹ together are — (CH ₂ ) _n −, where n is 2 or 3 and R ²² is hydrogen or alkyl;

(u) -NHC (X) NR ²³ R ²⁴ , wherein X is -O- or -S- and R ²³ and R ²⁴ are independently of each other hydrogen, alkyl or heteroalkyl;

(v) -CONR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R ²⁵ and R ²⁶ represent the nitrogen to which they are attached; Together form an optionally substituted heterocyclyl ring);

(w) —S (O) _n R ²⁷ where n is an integer from 0 to 2 and R ²⁷ is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or —NR ²⁸ R ²⁹ (where R ²⁸ and R ²⁹ is independently of each other hydrogen, alkyl or heteroalkyl);

(x) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl optionally substituted with alkyl, halo, hydroxy or amino;

(y) arylaminoalkylene or heteroarylaminoalkylene;

(z) Z-alkylene-NR ³⁰ R ³¹ or Z-alkylene-OR ³² wherein Z is -NH-, -N (lower alkyl)-or -O-, R ³⁰ , R ³¹ and R ³² are independently of each other hydrogen, alkyl or heteroalkyl;

(aa) -OC (O) -alkylene-CO ₂ H or -OC (O) -NR'R ", wherein R 'and R" are independently hydrogen or alkyl;

(bb) heteroarylalkenylene or heteroarylalkynylene;

(cc) hydrogen;

(dd) halo;

(ee) pseudohalo;

(ff) hydroxy;

(gg) optionally substituted alkoxy;

(hh) C (L) R ⁴⁰ wherein L is O, S or NR ⁵⁵ ; R ⁴⁰ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally Substituted heteroaryl, optionally substituted heteroaryllium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C (L) R ⁵⁶ , halo, pseudohalo, OR ⁵⁵ , SR ⁵⁵ , NR ⁵⁷ R ⁵⁸ or SiR ⁵² R ⁵³ R ⁵⁴ ; wherein in the definition of R ⁵² , R ⁵³ and R ⁵⁴ , (i) R ⁵² , R ⁵³ and R ⁵⁴ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl , Heteroaryllium, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶² R ⁶³ ; or (ii) any two of R ⁵² , R ⁵³ and R ⁵⁴ together are alkylene, alkenylene, alkynylene, hetero form an alkylene and the other is (i) selected from and; R ⁵⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl volume, cycloalkyl or hete Heterocyclyl, and; R ⁵⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl volume, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶⁴ R ⁶⁵ a; where R ⁶⁴ and R ⁶⁵ are each Independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁶⁶ or NR ⁶² R ⁶³ , or R ⁶⁴ and R ⁶⁵ together are alkylene, alkenylene , Alkynylene, heteroalkylene, wherein R ⁶⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl or heterocyclyl; in the definition of R ⁵⁷ and R ⁵⁸ , (i) R ⁵⁷ and R ⁵⁸ are each independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁵⁵ , NR ⁶⁷ R ⁶⁸ or C (L) R ⁶⁹ , wherein R ⁶⁷ and R ⁶⁸ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, Heteroaryl, heteroaryllium, cycloalkyl or heterocyclyl, or together they form alkylene, alkenylene, alkynylene, heteroalkylene; R ⁶⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁷⁰ or NR ⁶² R ⁶³ , wherein R ⁷⁰ is alkyl, alkenyl, alkynyl, Aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl; Or (ii) R ⁵⁷ and R ⁵⁸ together form alkylene, alkenylene, alkynylene, heteroalkylene, or alkyleneoxyalkylene; R ⁶² and R ⁶³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, or R ⁶² and R ⁶³ together are alkylene, alkenylene, Alkynylene, forms heteroalkylene); And

(ii) optionally substituted alkyl

It is selected from the group consisting of;

R ⁴ is

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) alkoxy; And

(e) hydroxy

It is selected from the group consisting of;

R ⁵ is

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) haloalkyl;

(e) thioalkyl;

(f) hydroxy;

(g) amino;

(h) alkylamino;

(i) dialkylamino;

(j) heteroalkyl;

(k) optionally substituted heterocycle;

(l) optionally substituted heterocyclylalkyl;

(m) optionally substituted heterocyclylalkoxy;

(n) alkylsulfonyl;

(o) aminosulfonyl, mono-alkylaminosulfonyl or di-alkylaminosulfonyl;

(p) heteroalkoxy; And

(q) carboxy

It is selected from the group consisting of;

R ⁶ is

(a) hydrogen;

(b) halo;

(c) alkyl; And

(d) alkoxy

It is selected from the group consisting of.

Also provided herein are pharmaceutical compositions containing a compound provided herein together with a pharmaceutically acceptable carrier.

Provided are methods of treating, preventing or alleviating one or more symptoms of cytokine mediated diseases in a mammal by administering a compound of Formula (I) to a mammalian patient in need thereof. Diseases and disorders that are treated, prevented or alleviate the symptoms thereof include, but are not limited to, chronic inflammatory diseases, inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease and congestive heart failure Do not.

Also provided are methods of preventing or inhibiting an inflammatory response using the compounds and compositions provided herein.

Further provided are methods of inhibiting p38 kinases including p38α and p38β kinases using the compounds and compositions provided herein.

Packaging materials, compounds or compositions provided herein useful for treating, preventing or alleviating one or more symptoms of a p38 kinase-mediated disease or disorder, and wherein the compounds or compositions treat one or more symptoms of a p38 kinase-mediated disease or disorder An article of manufacture comprising a label indicating useful for preventing or mitigating.

A. Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, published applications and publications, Genbank sequences, databases, websites, and other publications mentioned throughout the entire disclosure of this application are incorporated herein by reference in their entirety unless otherwise indicated. In the event that there are a plurality of definitions for a term herein, the definition in this section prevails. When referring to a URL or other such as an identifier or address, such an identifier may change and certain information on the Internet may change but an equivalent search may be found by Internet search. References to this Demonstrate the availability and public dissemination of this information.

As used herein, p38α is described by Han et al. (1995) Biochim . Biophys . Acta 1265 (2-3) : 224-7]. As used herein, p38β is described by Jiang et al. (1996) J. Biol . Chem . 271 (30) : 17920-6]. As used herein, p38γ is described in Li et al. (1996) Biochem . Biophys . Res. Commun . 228 : 334-340. As used herein, p38δ is described by Wang et al. (1997) J. Biol . Chem . 272 (38 ): 23668-74.

Pharmaceutically acceptable derivatives of the compounds as used herein include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. . Such derivatives can be readily prepared by those skilled in the art using known derivatization methods. The compounds prepared can be administered to animals or humans without substantial toxic effects and are pharmaceutically active or prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts such as, but not limited to, N, N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl Glucamine, Procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydr Oxymethyl) aminomethane; Alkali metal salts such as but not limited to lithium, potassium and sodium salts; Alkaline earth metal salts such as but not limited to barium, calcium and magnesium salts; Transition metal salts such as but not limited to zinc salts; And other metal salts such as but not limited to sodium hydrogen phosphate and disodium phosphate; But also includes, but is not limited to, nitrates, borates, methanesulfonates, benzenesulfonates, toluenesulfonates, inorganic acid salts such as but not limited to hydrochloride, hydrobromide, hydroiodide and sulfates; And organic acid salts such as but not limited to acetate, trifluoroacetate, oxalate, benzoate, salicylate, maleate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerian Rate and fumarate. It is also possible to form amphoteric ions (“in-molecular salts”). In certain embodiments, the salt form of the compound improves the dissolution rate and oral bioavailability of the compound. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, of acidic groups including carboxylic acid, phosphoric acid, phosphinic acid, sulfonic acid, sulfinic acid and boronic acid, Cycloalkyl and heterocyclyl esters, including but not limited to. Pharmaceutically acceptable enol ethers are of the formula C = C (OC (O) R), wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocycle Derivatives of aryl), including but not limited to. Pharmaceutically acceptable enol esters are derivatives of C═C (OR) wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl Including but not limited to. Pharmaceutically acceptable solvates and hydrates include one or more solvents or water molecules, or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3, or 4 solvents or water molecules. And a complex of compounds.

"Alkyl" means a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms, for example methyl, ethyl, propyl, 2-propyl, pentyl Etc.

The term "cycloalkyl" preferably means a saturated or partially unsaturated non-aromatic cyclic hydrocarbon ring system containing 1 to 3 rings and 3 to 7 carbons per ring, wherein the ring is further unsaturated C _3- Can be fused with a C ₇ carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. "Substituted cycloalkyl" is substituted with one or more groups described above with one or more alkyl or substituted alkyl groups or alkyl substituents described above. The expression "lower cycloalkyl" means an unsubstituted saturated or unsaturated non-aromatic cyclic hydrocarbon ring system containing 3 to 5 carbon atoms.

"Alkylene" means a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms, examples being methylene, ethylene, propylene, 2-methylpropylene , Pentylene and the like.

"Alkenyl" means a linear monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3 to 6 carbon atoms, for example ethenyl, propenyl Etc.

"Alkenylene" refers to a linear divalent hydrocarbon radical of 2 to 6 carbon atoms containing one or more double bonds or a branched divalent hydrocarbon radical of 3 to 6 carbon atoms, such as ethenylene, propenylene and the like. it means.

"Alkynyl" means a linear monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched divalent hydrocarbon radical of 3 to 6 carbon atoms containing one or more triple bonds, for example ethynyl, propynyl Etc.

"Alkynylene" means a linear monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms containing one or more triple bonds, for example ethynylene, propynylene Etc.

"Alkoxy" means a radical -OR where R is alkyl as described above, such as methoxy, ethoxy, propoxy, 2-propoxy and the like.

"Acyl" refers to the radical -C (O) R, wherein R is alkyl or haloalkyl, such as acetyl, trifluoroacetyl, and the like.

"Acyl amino" means a radical -NRC (O) R 'wherein R is hydrogen or alkyl and R' is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, for example acetylamino, 2-amino-2-methylpropionamide and the like.

"Halo" means fluoro, chloro, bromo, or iodo, generally fluoro and chloro.

"Haloalkyl" means alkyl substituted with one or more identical or different halo atoms, for example -CH ₂ Cl, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CC1 ₃ Etc.

"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical having 6 to 10 ring atoms, for example phenyl, 1-naphthyl, 2-naphthyl and the like. The aryl ring can optionally be fused with a 5-, 6- or 7-membered monocyclic saturated ring containing one or two heteroatoms independently selected from oxygen, nitrogen or sulfur, with the remaining ring atoms being C Wherein one or two C atoms may be optionally substituted with a carbonyl group. Representative aryl moieties having fused rings include 2,3-dihydrobenzo [1,4] dioxane, chroman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran , Benzo [1,3] dioxol, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-lH-indole, 2,3- Dihydro-lH-isoindole, benzimidazol-2-one, 3H-benzoxazol-2-one, and the like.

“Heteroaryl” contains 1, 2 or 3 ring heteroatoms selected from N, 0, or S and the remaining ring atoms are C 1 to monovalent monocyclic or bicyclic aromatic rings having 5 to 10 ring atoms. Means radicals. The term also includes radicals in which, for example, heteroatoms in the ring are oxidized or quaternized to form N-oxides or quaternary salts. Representative examples include thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, Benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl, pyrazinyl, pyridazino Nyl, pyrimidinyl, oxazoloyl, and their corresponding N-oxides (eg, pyridyl N-oxides, quinolinyl N-oxides), quaternary salts thereof, and the like, and the like. Does not.

"Heterocycle" or "heterocyclyl" means a cyclic non-aromatic radical having 3 to 8 ring atoms, wherein one or two ring atoms are N, 0, or S (O) _n (where n is an integer from 0 to 2), and the remaining ring atoms are C, wherein one or two C atoms are optionally substituted with a carbonyl group. The term also includes, for example, radicals in which ring nitrogen atoms are oxidized or quaternized to form N-oxides or quaternary salts. Representative examples include tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidino, morpholino, piperazino, pyrrolidino, oxiranyl, dioxane, 1,3-dioxolanyl, 2, 2-dimethyl-1,3-dioxalanyl, sulfonyl, 2-oxazolidonyl, 2-imidazolidonyl, S, S-dioxo-thiomorpholino, and the like. Do not.

"Heterocycloamino" means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N, contains one additional ring atom, optionally selected from N or O, and the remaining ring atoms Is C. The term includes groups such as pyrrolidino, piperidino, morpholino, piperazino and the like.

"Optionally substituted alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl" is independently alkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halo, cyano, heterocyclyl, acyl, -OR Wherein R is hydrogen or alkyl, -NRR 'wherein R and R' are independently selected from hydrogen or acyl or alkyl optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl, -NHCOR, where R is alkyl optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl, -NRS (O) _n R 'where R is hydrogen or alkyl and n is 0 to 2 R 'is hydrogen, alkyl or heteroalkyl and optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl, -NRS (O) _n NR'R "where R is hydrogen or alkyl N is an integer from 0 to 2; R 'and R "are independently hydrogen, alkyl or heteroalkyl and optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl), -S (O) _n R where n is an integer from 0 to 2; R is hydrogen, alkyl or heteroalkyl and hydroxy, alkoxy, cyano , Optionally substituted with halo or heterocyclyl, -S (O) _n NRR 'wherein n is an integer from 0 to 2; R and R' are independently hydrogen, alkyl or heteroalkyl, hydroxy, alkoxy , Optionally substituted with cyano, halo or heterocyclyl), -COOR,-(alkylene) COOR, wherein R is hydrogen or alkyl, -CONR'R "or-(alkylene) CONR'R" ( Wherein R ′ and R ″ are independently hydrogen or alkyl, or together with the nitrogen atom to which they are attached form an alkyl, alkenyl as described above optionally substituted with one or two substituents selected from); , Alkynyl, alkoxy or cycloalkyl group.

"Optionally substituted aryl, heteroaryl or heterocyclyl" independently refers to alkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halo, cyano, acyl, -OR (Where R is hydrogen or alkyl), -NRR '(where R and R' are independently selected from hydrogen, alkyl or acyl), -NHCOR (where R is alkyl), -NRS (O) _n R 'wherein R is hydrogen or alkyl, n is an integer from 0 to 2, and R' is hydrogen, alkyl or heteroalkyl, -NRS (O) _n NR'R "where R is hydrogen or Alkyl, n is an integer from 0 to 2, R 'and R "are independently hydrogen, alkyl or heteroalkyl), -S (O) _n R (where n is an integer from 0 to 2, R is Hydrogen, alkyl or heteroalkyl, -S (O) _n NRR 'where n is an integer from 0 to 2 and R and R' are independently hydrogen, alkyl or heteroalkyl, -COOR,-( Alkylene) COOR, wherein R is hydrogen or alkyl, -CONR'R "or-(alkylene) CONR'R", wherein R 'and R "are independently hydrogen or alkyl Aryl, he, as described above, optionally substituted with 4 or 2 substituents It means Loa reel or heterocyclyl ring.

"Heteroalkyl" means -NR ^a R ^b , -OR ^c Wherein one, two or three substituents are selected from R ^a , R ^b and R ^c independently of one another are hydrogen, alkyl or acyl, or R ^a and R ^b together form a heterocycloamino group Containing alkyl radicals as described above. Representative examples include hydroxymethyl, acetoxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-acetylaminoethyl, 3 -[Pyrrolidin-1-yl] ethyl and the like.

"Heteroalkenyl" is -NR ^a R ^b , -OR ^c or -S (O) _n R ^d where R ^a , R ^b and R ^c are independently of each other hydrogen or alkyl, and R ^d is alkyl or- An alkenyl radical as described above containing one or two substituents selected from NRR 'wherein R and R' are independently of one another hydrogen or alkyl. Representative examples include, but are not limited to, 3-hydroxy-1-propenyl, 3-aminoprop-1-enyl, 2-aminosulfonylethenyl, 2-methylsulfonylethenyl, and the like.

"Heteroalkynyl" refers to -NR ^a R ^b , -OR ^c , —S (O) _n R ^d or —S (O) _n NRR ′ wherein R and R ′ are independently of each other hydrogen or alkyl, R ^a , R ^b and R ^c are independently of each other hydrogen or alkyl, R ^d is alkyl and n is an integer from 0 to 2), meaning an alkynyl radical as described above containing one or two substituents. Representative examples include, but are not limited to, 3-hydroxy-1-propynyl, 3-dimethylaminoprop-1-ynyl, and the like.

"Heteroalkoxy" means a radical -OR where R is a heteroalkyl group as defined above, for example 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3--dihydroxyprop Foxy, 2-aminoethoxy and the like.

"Heteroalkylamino" means a radical -NR ^a R ^b where R ^a is hydrogen or alkyl as defined above and R ^b is a heteroalkyl group as defined above, for example 2-hydroxyethylamino, 3-dimethylaminopropylamino and the like.

"Optionally substituted heterocyclylalkyl" means a radical -R ^a R ^b where R ^a is an alkylene group as defined above and R ^b is an optionally substituted heterocyclyl group as defined above, for example 2- (morpholin-4-yl) ethyl, 3- (piperidin-1-yl) -2-methylpropyl, and the like.

"Optionally substituted heterocyclylalkenyl" means a radical -R ^a R ^b where R ^a is an alkenylene group as defined above and R ^b is an optionally substituted heterocyclyl group as defined above, eg Is 3- (morpholin-4-yl) prop-1-enyl, 3- (piperidin-1-yl) prop-1-enyl, 3- (4-methylpiperazin-1-yl) prop P-1-enyl and the like.

"Optionally substituted heterocyclylalkynyl" means a radical -R ^a R ^b where R ^a is an alkynyl group and R ^b is an optionally substituted heterocyclyl group as defined above, such as 3 -(Morpholin-4-yl) prop-1-ynyl, 3- (piperidin-1-yl) prop-1-ynyl and the like.

"Optionally substituted heterocyclylalkoxy" means a radical -OR where R is an optionally substituted heterocyclylalkyl group as defined above, for example 2- (morpholin-4-yl) -ethoxy , 3- (piperazin-1-yl) propoxy, 2- [2-oxopyrrolidin-1-yl] ethoxy and the like.

“Optionally substituted heterocyclylalkylamino” means a radical —NR ^a R ^b where R ^a is hydrogen or alkyl as defined above and R ^b is an optionally substituted heterocyclylalkyl group as defined above, Examples include 2- (pyrrolidin-2-yl) ethylamino, 3- (piperidin-1-yl) propylamino and the like.

"Optionally substituted heteroaralkyloxy" means a radical -OR ^a where R ^a is a heteroaralkyl radical, for example 2- (pyridin-3-yl) ethoxy, 2- [3 ( 2H) -pyridazol-1-yl] ethoxy and the like.

“Arbitrarily” or “optionally” means that the event or situation described subsequently may not need to occur and includes cases where and when events and situations do not occur. For example, “an aryl group optionally mono- or di-substituted with an alkyl group” does not necessarily require alkyl to exist, and this description does not indicate that the heterocyclo group is substituted with an alkyl group when the aryl group is mono- or di-substituted with an alkyl group. It includes if not.

"Amino protecting group" means an organic group that protects the nitrogen atom against undesirable reactions during the synthesis procedure, such as benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoro Acetyl and the like.

Throughout the specification, groups and substituents thereof may be selected by those skilled in the art to obtain stable residues and compounds. It is understood that the chemical groups described herein may be optionally substituted, unsubstituted, branched or unbranched.

All stereoisomers of the compounds provided herein are contemplated in the form of mixtures or in pure or substantially pure form. Definitions of compounds provided herein include all possible stereoisomers and mixtures thereof. It includes isolated optical isomers with racemic morphology and specific activity. Lamise forms can be separated by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by conventional methods such as salt formation with optically active acids, subsequent crystallization.

The compounds provided herein may also have prodrug forms. Any compound that is converted in vivo to provide a bioactive agent is a prodrug. Various forms of prodrugs are well known in the art. Examples of such prodrug derivatives are, for example, each of which is incorporated herein by reference.

a) in the Design of Prodrug , edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology , Vol. 42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, p. 113-191 (1991); And

c) H. Bundgaard, Advanced Drug Delivery Reviews , 8, 1-38 (1992).

As used herein, treatment means any way of alleviating or otherwise advantageously altering one or more symptoms of a disease or disorder. Treatment also includes pharmaceutical uses of the compounds and compositions herein, such as p38 kinase mediated diseases or disorders, or for treating diseases or disorders in which p38 kinase activity is associated, including p38α and p38β kinase activities.

As used herein, alleviation of the symptoms of a particular disorder by the administration of a particular compound or pharmaceutical composition means any alleviation that may be due to or associated with the administration of the composition, whether permanent or temporary, continuous or temporary. do.

As used herein, IC ₅₀ refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition (eg, modification of p38α kinase activity) of the maximal response in the assay measuring the response.

B. compound

Compounds provided herein for use in the compositions and methods are active in assays that measure p38 kinase activity, including but not limited to p38α and p38β kinase activity. In one embodiment, the compounds provided herein include a compound of Formula (I) or a pharmaceutically acceptable derivative thereof.

In the formula,

R ¹ is hydrogen, acyl or —P (O) (OH) ₂ ;

R ² is hydrogen, halo, alkyl or alkylthio;

A is a heterocyclyl ring optionally fused to an aryl, heteroaryl, or phenyl ring, provided that the heterocyclyl ring is attached to a carbonyl group via a carbon ring atom;

B is an aryl or heteroaryl ring;

C is a 5 membered heteroaryl ring containing 1 or 2 heteroatoms in the ring;

D is heteroaryl, optionally substituted heteroaryl, or -C (O) NR ⁸⁰ R ⁸¹ , wherein R ⁸⁰ and R ⁸¹ are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted hetero Aryl;

R ³ is

(a) amino, alkylamino or dialkylamino;

(b) acylamino;

(c) optionally substituted heterocyclyl;

(d) optionally substituted aryl or heteroaryl;

(e) heteroalkyl;

(f) heteroalkenyl;

(g) heteroalkynyl;

(h) heteroalkoxy;

(i) heteroalkylamino;

(j) optionally substituted heterocyclylalkyl;

(k) optionally substituted heterocyclylalkenyl;

(l) optionally substituted heterocyclylalkynyl;

(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy;

(n) optionally substituted heterocyclylalkylamino;

(o) optionally substituted heterocyclylalkylcarbonyl;

(p) heteroalkylcarbonyl;

(q) -NHSO ₂ R ⁶ , wherein R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;

(r) -NHSO ₂ NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently of each other hydrogen, alkyl or heteroalkyl;

(s) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O-, -NH- or -S (O) _n -where n is an integer from 0 to 2; R ⁹ is halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -COOH, -COR ¹⁰ , -COOR ¹¹ , -CONR ¹² R ¹³ , -SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ^17, or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹⁰ is alkyl or optionally substituted heterocycle, R ¹¹ is alkyl, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl);

(t) -C (= NR ²⁰ ) (NR ²¹ R ²² ), where R ²⁰ , R ²¹ And R ²² independently represents hydrogen, alkyl or hydroxy, or R ²⁰ And R ²¹ together are — (CH ₂ ) _n −, where n is 2 or 3 and R ²² is hydrogen or alkyl;

(u) -NHC (X) NR ²³ R ²⁴ , wherein X is -O- or -S- and R ²³ and R ²⁴ are independently of each other hydrogen, alkyl or heteroalkyl;

(v) -CONR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R ²⁵ and R ²⁶ represent the nitrogen to which they are attached; Together form an optionally substituted heterocyclyl ring);

(w) —S (O) _n R ²⁷ where n is an integer from 0 to 2 and R ²⁷ is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or —NR ²⁸ R ²⁹ (where R ²⁸ and R ²⁹ is independently of each other hydrogen, alkyl or heteroalkyl);

(x) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl optionally substituted with alkyl, halo, hydroxy or amino;

(y) arylaminoalkylene or heteroarylaminoalkylene;

(z) Z-alkylene-NR ³⁰ R ³¹ or Z-alkylene-OR ³² wherein Z is -NH-, -N (lower alkyl)-or -O-, R ³⁰ , R ³¹ and R ³² are independently of each other hydrogen, alkyl or heteroalkyl;

(aa) -OC (O) -alkylene-CO ₂ H or -OC (O) -NR'R ", wherein R 'and R" are independently hydrogen or alkyl;

(bb) heteroarylalkenylene or heteroarylalkynylene;

(cc) hydrogen;

(dd) halo;

(ee) pseudohalo;

(ff) hydroxy;

(gg) optionally substituted alkoxy;

(hh) C (L) R ⁴⁰ wherein L is O, S or NR ⁵⁵ ; R ⁴⁰ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally Substituted heteroaryl, optionally substituted heteroaryllium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C (L) R ⁵⁶ , halo, pseudohalo, OR ⁵⁵ , SR ⁵⁵ , NR ⁵⁷ R ⁵⁸ or SiR ⁵² R ⁵³ R ⁵⁴ , wherein in the definition of R ⁵² , R ⁵³ and R ⁵⁴ , (i) R ⁵² , R ⁵³ and R ⁵⁴ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, Heteroaryllium, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶² R ⁶³ ; or (ii) any two of R ⁵² , R ⁵³ and R ⁵⁴ together are alkylene, alkenylene, alkynylene, heteroalkyl Ene, the other is selected from (i); R ⁵⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl or hetero Cyclyl; R ⁵⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶⁴ R ⁶⁵ , wherein R ⁶⁴ and R ⁶⁵ are each Independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁶⁶ or NR ⁶² R ⁶³ , or R ⁶⁴ and R ⁶⁵ together are alkylene, alkenylene , Alkynylene, heteroalkylene, wherein R ⁶⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl or heterocyclyl; in the definition of R ⁵⁷ and R ⁵⁸ , (i) R ⁵⁷ and R ⁵⁸ are each independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁵⁵ , NR ⁶⁷ R ⁶⁸ or is C (L) R ^69, where R ⁶⁷ and R ⁶⁸ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, Interrogating aryl, heteroaryl of cerium, or a cycloalkyl or heterocyclyl, or they together form alkylene, alkenylene, alkynylene, hetero alkylene; R ⁶⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁷⁰ or NR ⁶² R ⁶³ , wherein R ⁷⁰ is alkyl, alkenyl, alkynyl, Aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl; Or (ii) R ⁵⁷ and R ⁵⁸ together form alkylene, alkenylene, alkynylene, heteroalkylene, or al cheyleneoxyalkylene; R ⁶² and R ⁶³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, or R ⁶² and R ⁶³ together are alkylene, alkenylene, Alkynylene, forms heteroalkylene); And

(ii) optionally substituted alkyl

It is selected from the group consisting of;

R ⁴ is

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) alkoxy; And

(e) hydroxy

It is selected from the group consisting of;

R ⁵ is

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) haloalkyl;

(e) thioalkyl;

(f) hydroxy;

(g) amino;

(h) alkylamino;

(i) dialkylamino;

(j) heteroalkyl;

(k) optionally substituted heterocycle;

(l) optionally substituted heterocyclylalkyl;

(m) optionally substituted heterocyclylalkoxy;

(n) alkylsulfonyl;

(o) aminosulfonyl, mono-alkylaminosulfonyl or di-alkylaminosulfonyl;

(p) heteroalkoxy; And

(q) carboxy

It is selected from the group consisting of;

R ⁶ is

(a) hydrogen;

(b) halo;

(c) alkyl; And

(d) alkoxy

It is selected from the group consisting of.

In one embodiment, C is a 5 membered heteroaryl ring containing 1 or 2 heteroatoms in the ring. In another embodiment, C is selected from pyrazole, imidazole, pyrrole, thiazole, isothiazole, oxazole, isoxazole, furan and thiophene ring. In another embodiment, C is a pyrazole or imidazole ring. In another embodiment, C is an imidazole ring. In another embodiment, C is a pyrazole ring.

One. Pyrazole -Based compounds

In one embodiment, C is a pyrazole ring and the compounds provided herein include a compound of Formula (II) or a pharmaceutically acceptable derivative thereof.

Wherein the variables are as defined above herein.

In this embodiment, the hydrogen of the ring NH group is a substituent represented in the structure (ie, -C (O) -A (R ³ ) (R ⁴ ), -R ² or -B (D) (R ⁶ ) (R ⁵ ) It may be substituted with one of)).

In another embodiment, a compound provided herein comprises a compound of Formula III or a pharmaceutically acceptable derivative thereof.

Wherein the variables are as defined above herein.

In another embodiment, a compound provided herein comprises a compound of Formula IV or a pharmaceutically acceptable derivative thereof.

Wherein the variables are as defined above herein.

In another embodiment, the compounds provided herein include a compound of Formula (V) or a pharmaceutically acceptable derivative thereof.

Wherein the variables are as defined above herein.

In another embodiment, a compound provided herein comprises a compound of Formula Va or a pharmaceutically acceptable derivative thereof.

In the formula, A, D, R ³ , R ⁴ , And R ⁶ is as defined above herein.

2. Imidazole-based compounds

In another embodiment, the compound is an imidazole-based compound of Formula VI or a pharmaceutically acceptable derivative thereof.

Wherein the variables are as defined above herein.

In this embodiment, the hydrogen of the ring NH group is a substituent represented in the structure (ie, -C (O) -A (R ³ ) (R ⁴ ), -R ² or -B (D) (R ⁶ ) (R ⁵ ) It may be substituted with one of)).

In another embodiment, the compounds provided herein comprise a compound of Formula VII or a pharmaceutically acceptable derivative thereof.

Wherein the variables are as defined above herein.

In another embodiment, a compound provided herein comprises a compound of Formula VIII or a pharmaceutically acceptable derivative thereof.

Wherein the variables are as defined above herein.

3. Other embodiments

In other embodiments, the compounds for use in the compositions and methods provided herein include compounds of the above formula wherein R ¹ is hydrogen or a pharmaceutically acceptable derivative thereof. In another embodiment, R ² is hydrogen or lower alkyl. In another embodiment, R ² is hydrogen.

In another embodiment, G is OR ⁸³ or NR ⁸⁰ R ⁸¹ . In another embodiment, R ⁸³ is alkyl or cycloalkyl. In another embodiment, R ⁸³ is alkyl. In another embodiment, R ⁸³ is ethyl. In another embodiment, R ⁸⁰ and R ⁸¹ are each independently hydrogen, alkyl or cycloalkyl. In yet other embodiments, R ⁸⁰ and R ⁸¹ are each independently hydrogen or cycloalkyl. In another embodiment, R ⁸⁰ and R ⁸¹ are each independently hydrogen or cyclohexyl. In another embodiment, G is NH ₂ or NH (cyclohexyl).

In another embodiment, G is heterocyclyl optionally fused to aryl, heteroaryl, cycloalkyl, heterocyclyl, or phenyl, substituted with R ³ and R ⁴ , provided that the heterocyclyl ring represents a carbon ring atom Is attached via a carbonyl group. In another embodiment, G is phenyl, cyclohexyl, cyclopentyl or benzyl and is substituted with R ³ and R ⁴ . In another embodiment, G is phenyl and is substituted with R ³ and R ⁴ .

In another embodiment, A is an aryl ring. In another embodiment, A is a phenyl ring.

In another embodiment, B is an aryl ring. In another embodiment, B is a phenyl ring.

In another embodiment, D is —C (O) NR ⁸⁰ R ⁸¹ . In another embodiment, R ⁸⁰ and R ⁸¹ are each independently hydrogen, cycloalkyl or alkoxy. In another embodiment, R ⁸⁰ is hydrogen. In another embodiment, R ⁸¹ is cycloalkyl or alkoxy. In another embodiment, R ⁸¹ is C _{3 -} a _6-alkoxy-6 cycloalkyl or C _1. In another embodiment, R ⁸¹ is cyclopropyl or methoxy.

In another embodiment, D is optionally substituted heteroaryl. In another embodiment, D is optionally substituted triazolyl. In another embodiment, D is 1,2,4-triazol-3-yl.

In another embodiment, R ³ is hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C (L) R ⁴⁰ , halo, pseudohalo or OR ⁴¹ ; Wherein L is O, S or NR ⁵⁵ ; R ⁴⁰ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryllium, optionally substituted cycloalkyl, optionally substituted hetero Cyclyl, C (L) R ⁵⁶ , halo, pseudohalo, OR ⁵⁵ , SR ⁵⁵ , NR ⁵⁷ R ⁵⁸ or SiR ⁵² R ⁵³ R ⁵⁴ ; R ⁴¹ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryllium, optionally substituted cycloalkyl, optionally substituted Heterocyclyl, C (L) R ⁵⁹ , NR ⁶⁰ R ⁶¹ or SiR ⁵² R ⁵³ R ⁵⁴ ; Wherein in the definition of R ⁵² , R ⁵³ and R ⁵⁴ , (i) R ⁵² , R ⁵³ and R ⁵⁴ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, Heterocyclyl, OR ⁵⁵ or NR ⁶² R ⁶³ ; Or (ii) any two of R ⁵² , R ^53, and R ⁵⁴ together form alkylene, alkenylene, alkynylene, heteroalkylene, and the other is selected from (i); R ⁵⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl or heterocyclyl; R ⁵⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶⁴ R ⁶⁵ ; Wherein R ⁶⁴ and R ⁶⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁶⁶ or NR ⁶² R ⁶³ , or R ⁶⁴ and R ⁶⁵ together form alkylene, alkenylene, alkynylene, heteroalkylene, wherein R ⁶⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl or heterocyclyl; In the definition of R ⁵⁷ and R ⁵⁸ , (i) R ⁵⁷ and R ⁵⁸ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁵⁵ , NR ⁶⁷ R ⁶⁸ or C (L) R ⁶⁹ , wherein R ⁶⁷ and R ⁶⁸ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl or heterocyclyl, or Or they together form alkylene, alkenylene, alkynylene, heteroalkylene; R ⁶⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁷⁰ or NR ⁶² R ⁶³ , wherein R ⁷⁰ is alkyl, alkenyl, alkynyl, Aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl; Or (ii) R ⁵⁷ and R ⁵⁸ together form alkylene, alkenylene, alkynylene, heteroalkylene; R ⁵⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁷⁰ or NR ⁶² R ⁶³ ; R ⁶⁰ and R ⁶¹ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl or C (L) R ⁷¹ , wherein R ⁷¹ is alkyl, al Kenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, OR ⁵⁵ or NR ⁶² R ⁶³ ; Or R ⁶⁰ and R ⁶¹ together form an alkylene, alkenylene, alkynylene, heteroalkylene; R ⁶² and R ⁶³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryllium, cycloalkyl, heterocyclyl, or R ⁶² and R ⁶³ together are alkylene, alkenylene, Alkynylene, heteroalkylene.

In another embodiment, R ³ is hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C (L) R ⁴⁰ , halo or OR ⁴¹ . In another embodiment, R ³ is hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C (L) R ⁴⁰ , iodo, chloro or OR ⁴¹ . In another embodiment, R ³ is hydrogen, optionally substituted dioxolanyl, optionally substituted methyl, C (L) R ⁴⁰ , iodo, chloro or OR ⁴¹ . In another embodiment, R ³ is hydrogen, 2-dioxolanyl, optionally substituted methyl, C (O) R ⁴⁰ , iodo, chloro or OR ⁴¹ . In another embodiment, R ³ is hydrogen, 2-dioxolanyl, optionally substituted methyl, CHO, iodo, chloro or OR ⁴¹ . In another embodiment, R ³ is hydrogen.

In another embodiment, R ³ is optionally substituted methyl. In another embodiment, R ³ is methyl optionally substituted with heterocyclyl, hydroxy, aralkylamino or heterocyclylalkylamino. In another embodiment, R ³ is N -morpholinylmethyl, hydroxymethyl, N- (2- (3-chlorophenyl) -1-ethyl) aminomethyl, N- (2-morpholinyl-1- Ethyl) aminomethyl or 4-piperidinylmethyl.

In another embodiment, A is O. In another embodiment, R ⁴⁰ is hydrogen, optionally substituted alkyl or cycloalkyl. In another embodiment, R ⁴⁰ is hydrogen or alkyl. In another embodiment, R ⁴⁰ is hydrogen.

In another embodiment, R ⁴¹ is hydrogen or optionally substituted alkyl. In another embodiment, R ⁴¹ is hydrogen or alkyl optionally substituted with heterocyclyl, aryl, dialkylamino, halo or hydroxy. In another embodiment, R ⁴¹ is optionally substituted C ₁ is hydrogen, or heterocyclyl, phenyl, dialkylamino, halo or _hydroxy-3 is alkyl. In another embodiment, R ⁴¹ is hydrogen, 2- (N-morpholinyl) eth-1-yl, benzyl, 2- ( N, N -di- (2-hydroxy-1-ethyl) amino)- 1-ethyl, 2-bromo-1-ethyl, 2,2-dioxolan-4-ylmethyl, 2- (4-methylpiperazin-1-yl) -1-ethyl or 2,3-dihydroxy -1-propyl. In another embodiment, R ⁴¹ is ( S ) -2,3-dihydroxy-1-propyl.

In another embodiment, R ⁴ is hydrogen. In another embodiment, R ⁵ is alkyl. In another embodiment, R ⁵ is methyl. In another embodiment, R ⁶ is hydrogen.

In another embodiment, the compound for use in the compositions and methods provided herein

R ¹ is hydrogen, acyl or —P (O) (OH) ₂ ;

R ² is hydrogen, halo, alkyl or alkylthio;

A is a heterocyclyl ring optionally fused to an aryl, heteroaryl, or phenyl ring, provided that the heterocyclyl ring is attached to a carbonyl group via a carbon ring atom;

B is an aryl or heteroaryl ring;

D is heteroaryl, optionally substituted heteroaryl, or —C (O) NR ⁸⁰ R ⁸¹ wherein R ⁸⁰ and R ⁸¹ are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted hetero Aryl);

R ³ is

(a) amino, alkylamino or dialkylamino;

(b) acylamino;

(c) optionally substituted heterocyclyl;

(d) optionally substituted aryl or heteroaryl;

(e) heteroalkyl;

(f) heteroalkenyl;

(g) heteroalkynyl;

(h) heteroalkoxy;

(i) heteroalkylamino;

(j) optionally substituted heterocyclylalkyl;

(k) optionally substituted heterocyclylalkenyl;

(l) optionally substituted heterocyclylalkynyl;

(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy;

(n) optionally substituted heterocyclylalkylamino;

(o) optionally substituted heterocyclylalkylcarbonyl;

(p) heteroalkylcarbonyl;

(q) -NHSO ₂ R ⁶ , wherein R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;

(r) -NHSO ₂ NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently of each other hydrogen, alkyl or heteroalkyl;

(s) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O-, -NH- or -S (O) _n , wherein n is an integer from 0 to 2; R ⁹ Is cyano, optionally substituted heteroaryl, -COOH, -COR ¹⁰ , -COOR ¹¹ , -CONR ¹² R ¹³ , -SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ¹⁷ or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹⁰ is alkyl or optionally substituted heterocycle, R ¹¹ is alkyl, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl);

(t) -C (= NR ²⁰ ) (NR ²¹ R ²² ), where R ²⁰ , R ²¹ and R ²² independently represent hydrogen, alkyl or hydroxy, or R ²⁰ And R ²¹ together are — (CH ₂ ) _n −, where n is 2 or 3 and R ²² is hydrogen or alkyl;

(u) -NHC (X) NR ²³ R ²⁴ , wherein X is -O- or -S- and R ²³ and R ²⁴ are independently of each other hydrogen, alkyl or heteroalkyl;

(v) -CONR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R ²⁵ and R ²⁶ represent the nitrogen to which they are attached; Together form an optionally substituted heterocyclyl ring);

(w) —S (O) _n R ²⁷ where n is an integer from 0 to 2 and R ²⁷ is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or —NR ²⁸ R ²⁹ (where R ²⁸ and R ²⁹ is independently of each other hydrogen, alkyl or heteroalkyl);

(x) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl optionally substituted with alkyl, halo, hydroxy or amino;

(y) arylaminoalkylene or heteroarylaminoalkylene;

(z) Z-alkylene-NR ³⁰ R ³¹ or Z-alkylene-OR ³² wherein Z is -NH-, -N (lower alkyl)-or -O-, R ³⁰ , R ³¹ and R ³² are independently of each other hydrogen, alkyl or heteroalkyl;

(aa) -OC (O) -alkylene-CO ₂ H or -OC (O) -NR'R ", wherein R 'and R" are independently hydrogen or alkyl; And

(bb) heteroarylalkenylene or heteroarylalkynylene

It is selected from the group consisting of;

R ⁴ is

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) alkoxy; And

(e) hydroxy

It is selected from the group consisting of;

R ⁵

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) haloalkyl;

(e) thioalkyl;

(f) hydroxy;

(g) amino;

(h) alkylamino;

(i) dialkylamino;

(j) heteroalkyl;

(k) optionally substituted heterocycle;

(l) optionally substituted heterocyclylalkyl;

(m) optionally substituted heterocyclylalkoxy;

(n) alkylsulfonyl;

(o) aminosulfonyl, mono-alkylaminosulfonyl or di-alkylaminosulfonyl;

(p) heteroalkoxy; And

(q) carboxy

It is selected from the group consisting of;

R ⁶ is

(a) hydrogen;

(b) halo;

(c) alkyl; And

(d) alkoxy

Or a pharmaceutically acceptable derivative, prodrug, individual isomer, mixture of isomers and pharmaceutically acceptable salts thereof.

In another embodiment, the compound is

R ¹ is hydrogen or acyl;

R ² is hydrogen or alkyl;

A is a compound in which A is an aryl or heteroaryl ring.

In another embodiment, the compound is

R ¹ is hydrogen, acyl or —P (O) (OH) ₂ ;

R ² is hydrogen, halo, alkyl or alkylthio;

A is a heterocyclyl ring optionally fused to an aryl, heteroaryl or phenyl ring, provided that the heterocyclyl ring is attached to a carbonyl group via a carbon ring atom;

B is an aryl or heteroaryl ring;

R ³ is

(a) amino;

(b) acylamino;

(c) optionally substituted heterocycle;

(d) heteroaryl optionally substituted with substituents selected from halo, alkyl or alkoxy;

(e) heteroalkyl;

(f) heteroalkenyl;

(g) heteroalkynyl;

(h) heteroalkoxy

(i) heteroalkylamino;

(j) optionally substituted heterocyclylalkyl;

(k) optionally substituted heterocyclylalkenyl;

(l) optionally substituted heterocyclylalkynyl;

(m) optionally substituted heterocyclylalkoxy;

(n) optionally substituted heterocyclylalkylamino;

(o) optionally substituted heterocyclylalkylcarbonyl;

(p) heteroalkylcarbonyl;

(q) -NHSO ₂ R ⁶ , wherein R ⁶ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;

(r) -NHSO ₂ NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently of each other hydrogen, alkyl or heteroalkyl;

(s) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O-, -NH- or -S (O) _n -where n is an integer from 0 to 2; R ⁹ is cyano, heteroaryl, -COOH, -COR ¹⁰ , -COOR ¹¹ -CONR ¹² R ¹³ , -SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , NHSO ₂ R ¹⁷ Or —NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹⁰ is alkyl or optionally substituted heterocycle, R ¹¹ is alkyl, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl);

(t) -C (= NR ²⁰ ) (NR ²¹ R ²² ), where R ²⁰ , R ²¹ And R ²² independently represents hydrogen, alkyl or hydroxy, or R ²⁰ And R ²¹ together are — (CH ₂ ) _n −, where n is 2 or 3 and R ²² is hydrogen or alkyl;

(u) -NHC (X) NR ²³ R ²⁴ , wherein X is -0- or -S- and R ²³ and R ²⁴ are independently of each other hydrogen, alkyl or heteroalkyl;

(v) -CONR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R ²⁵ and R ²⁶ represent the nitrogen to which they are attached; Together form an optionally substituted heterocyclyl ring);

(w) —S (O) _n R ²⁷ where n is an integer from 0 to 2 and R ²⁷ is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or —NR ²⁸ R ²⁹ (where R ²⁸ And R ²⁹ are independently of each other hydrogen, alkyl or heteroalkyl)

It is selected from the group consisting of;

R ⁴ is

(a) hydrogen;

(b) halo;

(c) alkyl; And

(d) alkoxy

It is selected from the group consisting of;

R ⁵

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) haloalkyl;

(e) thioalkyl;

(f) hydroxy;

(g) amino;

(h) alkylamino;

(i) dialkylamino;

(j) heteroalkyl;

(k) optionally substituted heterocycle;

(l) optionally substituted heterocyclylalkyl; And

(m) optionally substituted heterocyclylalkoxy

It is selected from the group consisting of;

R ⁶ is

(a) hydrogen;

(b) halo;

(c) alkyl; And

(d) alkoxy

It is selected from the group consisting of.

In another embodiment, the compound is R ³ is

(a) optionally substituted heterocyclyl;

(b) halo, alkyl, amino, alkoxy, carboxy, lower alkoxy carbonyl, SO ₂ R 'where R' is alkyl, or -O ₂ NHR'R "where R 'and R" are independently Aryl or heteroaryl optionally substituted with a substituent selected from hydrogen or alkyl;

(c) heteroalkyl;

(d) heteroalkenyl;

(e) heteroalkylamino;

(f) heteroalkoxy;

(g) optionally substituted heterocyclylalkyl or heterocyclyloxy;

(h) optionally substituted heterocyclylalkenyl;

(i) optionally substituted heterocyclylalkynyl;

(j) optionally substituted heterocyclylalkoxy;

(k) optionally substituted heterocyclylalkylamino;

(l) optionally substituted heterocyclylalkylcarbonyl:

(s) -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O or -NH-, and R ⁹ is optionally substituted heteroaryl, -CONR ¹² R ¹³ , SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ -NHSO ₂ R ¹⁷ or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl);

(x) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl optionally substituted with alkyl, halo, hydroxy or amino;

(m) arylaminoalkylene or heteroarylaminoalkylene; or

(n) Z-alkylene-NR ³⁰ R ³¹ wherein Z is -NH-, -N (alkyl)-or -0- and R ³⁰ and R ³¹ are independently of each other hydrogen, alkyl or heteroalkyl

It is a compound selected from the group consisting of.

In another embodiment, the compound is a compound wherein R ¹ and R ² are hydrogen and B is phenyl. In a further embodiment, the compound is a compound wherein R ⁴ is hydrogen and R ⁵ is halo or alkyl. In another embodiment, the compound is a compound wherein R ⁵ is chloro, fluoro or methyl and R ⁶ is hydrogen, chloro, fluoro, methyl or methoxy. In another embodiment, the compound is a compound wherein R ³ is optionally substituted heteroaryl.

In another embodiment, the compound is a compound wherein R ³ is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxidopyridin-2-yl, N-oxidopyridin-3-yl, N Oxidopyridin-4-yl or pyridone-2-yl, all of which are optionally substituted. In further embodiments, the compound is a compound wherein R ³ is at the 3-position. In another embodiment, the compound is a compound wherein R ⁵ is 4-F or 2-Me and hydrogen is R ⁶ . In another embodiment, the compound is a compound wherein R ³ is optionally substituted phenyl.

In further embodiments, the compound is a compound wherein R ³ is 3-sulfamoylphenyl, 3--methylsulfonylphenyl, 3-carboxyphenyl or 3--ethoxycarbonylphenyl. In another embodiment, the compound is a compound wherein R ⁵ is 4-F and R ⁶ is hydrogen.

In another embodiment, the compound is R ³ is

(a) heteroalkyl;

(b) heteroalkoxy;

(c) heteroalkylamino;

(d) optionally substituted heterocyclylalkyl;

(e) optionally substituted heterocyclylalkoxy;

(f) optionally substituted heterocyclylalkylamino;

(g) Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O- or -NH-, R ⁹ is optionally substituted heteroaryl, -CONR ¹² R ¹³ , -SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ¹⁷ or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independent of each other Is hydrogen, alkyl or heteroalkyl); or

(h) Z-alkylene-NR ³⁰ R ³¹ wherein Z is -NH-, -N (alkyl)-or -O-, and R ³⁰ and R ³¹ are independently of each other hydrogen, alkyl or heteroalkyl

It is a compound selected from the group consisting of.

In further embodiments is a compound wherein Compound R ³ is heteroalkyl. In another embodiment, the compound is a compound wherein R ³ is in the 3-position, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 2-dimethylaminoethylamino, 3-dimethylaminopropylamino, Compound selected from the group consisting of hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methyl-1-butyl or 3-hydroxybutyl. In another embodiment, the compound is a compound wherein R ⁵ is 2-F and R ⁶ is 4-F.

In another embodiment, the compound is a compound wherein R ⁵ is 2-Me and R ⁶ is hydrogen. In further embodiments, the compound is a compound wherein R ⁹ is heteroalkoxy or heteroalkylamino. In another embodiment, the compound is a compound wherein R ³ is in the 3-position, 3-dimethylaminopropoxy, 2-dimethylaminoethoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 2 -Dimethylaminoethylamino and 3-dimethylaminopropylamino.

In another embodiment, the compound is a compound wherein R ³ is optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy or optionally substituted heterocyclylalkylamino. In another embodiment, the compound is a compound wherein R ³ is in the 3-position, 3- (morpholin-4-yl) propoxy, 2- (morpholin-4-yl) ethoxy, 2- (2-oxo -Pyrrolidin-1-yl) ethoxy, 3- (morpholin-4-yl) propyl, 2- (morpholin-4-yl) ethyl, 4- (morpholin-4-yl) butyl, 3- (Morpholin-4-yl) propylamino, 2- (morpholin-4-yl) ethylamino, 4-hydroxypiperidinylmethyl, 2- (S, S-dioxo-thiamorpholin-4-yl ) Ethyl, 3- (S, S-dioxo-thiamorpholin-4-yl) propyl and N-methylpiperazinylmethyl.

In a further embodiment, the compound wherein R ³ is -Y- (alkylene) -R ⁹ , wherein Y is a single bond, -O- or -NH-, and R ⁹ is optionally substituted heteroaryl, -CONR ¹² R ¹³ , -SO ₂ R ¹⁴ , -SO ₂ NR ¹⁵ R ¹⁶ , -NHSO ₂ R ¹⁷ or -NHSO ₂ NR ¹⁸ R ¹⁹ , wherein R ¹² , R ¹³ , R ¹⁴ _, R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ And R ¹⁹ are independently of each other hydrogen, alkyl or heteroalkyl. In further embodiments, the compound is a compound wherein Y is a single bond and R ⁹ is —SO ₂ R ¹⁴ or —SO ₂ NR ¹⁵ R ¹⁶ .

In further embodiments, the compound is a compound wherein R ³ is 5-methylsulfonylethyl or sulfamoylethyl.

Further, herein, 5-amino-1- (4-fluorophenyl) -4- [3- (2-morpholin-4-ylethoxy) -benzoyl] pyrazole, 5-amino-1- (2, 4-difluorophenyl) -4- [3- (3-morpholin-4-ylpropyl) benzoyl] pyrazole, 5-amino-4- (3-aminobenzoyl) -1- (4-fluorophenyl ) Pyrazole, 5-amino-1- (4-fluorophenyl) -4- [3- (3-morpholin-4-ylpropyl) -benzoyl] pyrazole, 5-amino-4- [3- ( 2-aminosulfonylethenyl) benzoyl] -1- (4-fluorophenyl) pyrazole, 5-amino-4- (3-acetylaminobenzoyl) -1-phenylpyrazole, 5-amino-4- [ 3- (2-aminoethyl) benzoyl] -1- (4-fluorophenyl) pyrazole, 5-amino-1- (4-fluorophenyl) -4- [3- (3-morpholine-4- Ylpropylamino) -benzoyl] pyrazole, 5-amino-4- [3- (2-aminosulfonylethyl) benzoyl] -1- (4-fluorophenyl) -pyrazole and 5-amino-1- ( Provided are compounds selected from the group consisting of 4-fluorophenyl) -4- (3-pyridin-3-ylbenzoyl) pyrazole.

Further, herein, 5-amino-1- (2-methylphenyl) -4- [3-pyridin-3-yl) benzoyl] pyrazole, 5-amino-1- (2-methylphenyl) -4- [3- ( N-oxidopyridin-3-yl) benzoyl] -pyrazole, 5-amino-4- [3- (2,3-dihydroxypropoxy) benzoyl] -1- (4-fluorophenyl) -pyra Sol, 5-amino-4- [3- (1,2-dihydroxyethyl) benzoyl] -1- (4-fluorophenyl) -pyrazole, 5-amino-1- (4-fluorophenyl) -4- [3- (sulfamoylbenzoyl] pyrazole, 5-amino-1- (4-fluorophenyl) -4- [3- (3-hydroxy-3-methylbutyl) -benzoyl] pyrazole, 5-amino-1- (4-fluorophenyl) -4- [3- (2- (1-hydroxycyclopentyl) ethyl) -benzoyl] pyrazole, 5-amino-4- [3- (2- Methylsulfonylethyl) benzoyl] -1- (4-fluorophenyl) -pyrazole, and 5-amino-1- (2,4-difluorophenyl) -4- [3- (2-hydroxyethyl Sulfonyl) -benzoyl] pyrazole is provided.

Further, herein, 3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -N-methoxy-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-pyrazol-1-yl) -N-methoxy-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-pyrazol-1-yl) -4-methyl-benzoic acid; 3- (5-Amino-4-benzoyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -4-methyl-benzoic acid; 3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; {5-Amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) -phenyl] -1 H-pyrazol-4-yl} -phenyl-methanone; 3- [5-amino-4- (3- [1,3] dioxolan-2-yl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-formyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-hydroxymethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (4-methyl-piperazin-1-ylmethyl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-morpholin-4-ylmethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-morpholin-4-ylmethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-benzyloxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-hydroxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-methyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; And 3- (5-amino-4-benzoyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide.

 Further, herein, 3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -N-methoxy-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-pyrazol-1-yl) -N-methoxy-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; {5-Amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) -phenyl] -1 H-pyrazol-4-yl} -phenyl-methanone; 3- [5-amino-4- (3- [1,3] dioxolan-2-yl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-formyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-hydroxymethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (4-methyl-piperazin-1-ylmethyl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-morpholin-4-ylmethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-morpholin-4-ylmethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-benzyloxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-hydroxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-methyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; Or 3- (5-amino-4-benzoyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide.

Also,

3- {5-Amino-4- [3- (2-dimethylamino-ethylcarbamoyl) -benzoyl] -imidazol-1-yl} -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (5-chloro-thiophen-2-carbonyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-hydrazinocarbonyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-cyclohexanecarbonyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-cyclopentanecarbonyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-phenylacetyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (tetrahydro-pyran-4-carbonyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-ethylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; And

Provided are compounds selected from 3- [5-amino-4- (3-isopropylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide.

Also,

5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester;

5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester;

3- (5-Amino-4-cyclopentanecarbonyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-hydrazinocarbonyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid benzylamide;

3- (5-Amino-4-cyclohexanecarbonyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; And

Provided are compounds selected from 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid cyclohexylamide.

Also,

5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide;

5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methanesulfonyl-1H-pyrazole-4-carboxylic acid amide;

5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester;

5-Amino-3-[(3-chloro-benzylcarbamoyl) -methoxy] -1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid Ethyl esters;

3- [5-amino-4-benzoyl-3- (piperidin-4-yloxy) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-benzoyl-3-methanesulfonyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-benzoyl-3-methoxy-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3- (2-hydroxy-ethoxy) -1 H-pyrazole-4-carboxylic acid ethyl ester;

4- [5-Amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazol-3-yloxy] -piperidine-1-carboxylic acid tert Butyl ester;

3- (5-Amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; And

There is provided a compound selected from 3- [5-amino-4-benzoyl-3- (2-methoxy-ethoxy) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide.

Also,

3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -N-methoxy-4-methyl-benzamide;

3- (5-Amino-4-benzoyl-pyrazol-1-yl) -N-methoxy-4-methyl-benzamide;

3- (5-Amino-4-benzoyl-pyrazol-1-yl) -4-methyl-benzoic acid;

3- (5-Amino-4-benzoyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- [5-Amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -4-methyl-benzoic acid;

3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

{5-Amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) -phenyl] -1 H-pyrazol-4-yl} -phenyl-methanone;

3- [5-amino-4- (3- [1,3] dioxolan-2-yl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-formyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-hydroxymethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- {5-Amino-4- [3- (4-methyl-piperazin-1-ylmethyl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-morpholin-4-ylmethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- {5-Amino-4- [3- (2-morpholin-4-yl-ethoxy) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-benzyloxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-Amino-4- (3-hydroxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (4-methyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-benzoyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-cyclohexanecarbonyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-cyclopentanecarbonyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-phenylacetyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- [5-Amino-4- (3-isopropylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- {5-Amino-4- [3- (2-dimethylamino-ethylcarbamoyl) -benzoyl] -imidazol-1-yl} -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-ethylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-methylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-cyclopropylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (3-cyclopentylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- {5-Amino-4- [3- (morpholin-4-carbonyl) -benzoyl] -imidazol-1-yl} -N-cyclopropyl-4-methyl-benzamide;

3- {5-Amino-4- [3- (cyclopropylmethyl-carbamoyl) -benzoyl] -imidazol-1-yl} -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4- (tetrahydro-pyran-4-carbonyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-benzoyl-3-methoxy-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-benzoyl-3-ethoxy-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4-benzoyl-3- (2-methoxy-ethoxy) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

3- [5-amino-4-benzoyl-3- (2-benzyloxy-ethoxy) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide;

4- [5-Amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazol-3-yloxy] -piperidine-1-carboxylic acid tert Butyl ester;

3- [5-amino-4-benzoyl-3- (piperidin-4-yloxy) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide, trifluoroacetate salt;

3- (5-Amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

3- (5-Amino-4-benzoyl-3-methanesulfonyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide;

5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide;

5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methanesulfonyl-1H-pyrazole-4-carboxylic acid amide; And

Provided are compounds selected from 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester.

C. Preparation of compounds

In addition, in this application

(i) to obtain a compound of general formula (I) of the 2-keto-3-phenylamino-reacted with a hydrazine of formula (2) acrylonitrile R ¹ is hydrogen the formula I, or

(ii) reacting 2-keto-3-phenylaminoacrylonitrile of formula ( 3 ) with hydrazine of formula ( 2 ) to give a compound of formula ( 4 ), and then converting the Z group to the desired R ³ group so that R ¹ is hydrogen; Obtaining the compound of claim,

(iii) optionally modifying any R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ group,

(iv) optionally treating the compound of formula (I) prepared in steps (i), (ii) or (iii) with an acid to convert it to the corresponding acid addition salt,

(v) optionally treating the compound of formula (I) prepared in steps (i), (ii) or (iii) with a base to convert it to the corresponding free base, and

(vi) optionally isolating a mixture of stereoisomers of the compounds of formula (I) prepared in steps (i) to (v) to obtain a single stereoisomer

It provides a method for producing a compound of formula (I) comprising.

In the formula,

R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above,

Z is a hydroxy, nitro or halo group.

Also,

(여기서, R³ 및 R⁴는 상기 정의된 바와 같고, M은 비제한적으로 알칼리 금속, 알칼리 토금속 및 전이금속, 예컨대 Li, K 및 Mg를 비롯한 금속 잔기임)의 유기금속 시약과 반응시켜 R¹이 수소인 화학식 I의 화합물을 수득하는 단계,(i) Compounds of formula 5 are formulated under organometallic substitution reaction conditions, including but not limited to halo, pseudohalo, aryloxy, perfluoroaryloxy, N-alkoxyamino (including N-methoxyamino)

It is reacted with an organometallic reagent (where, R ³ and R ⁴ are as defined above, M is not limited to, alkali metals, alkaline earth metals and transition metals such as Li, K, and the metal moiety being, including Mg) R ¹ Obtaining a compound of formula (I) which is hydrogen

(ii) optionally modifying any R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ group,

(iii) optionally treating the compound of formula (I) prepared in step (i) or (ii) with an acid to convert it to the corresponding acid addition salt,

(iv) optionally treating the compound of formula (I) prepared in step (i) or (ii) with a base to convert it to the corresponding free base, and

Optionally separating the mixture of stereoisomers of the compounds prepared in steps (i) to (iv) to obtain a single stereoisomer

It provides a method for producing a compound of formula (I) comprising.

In the formula,

R ⁵ and R ⁶ are as defined above,

L is a leaving group.

The compounds disclosed herein are merely exemplary and one skilled in the art can readily prepare the compounds in the same manner disclosed herein using well known chemical synthesis methods, including methods similar to those exemplified herein.

Compounds provided herein can be conventionally prepared according to the following schemes and the knowledge of those skilled in the art. Further synthesis methods are described, for example, in US Pat. No. 6,376,527; 6,316,466 and 6,444,696, and International Patent Application Publication No. WO 99/57101, which are incorporated herein by reference.

In addition to the literature cited by reference, the inventors disclose non-limiting examples of methods useful for the preparation of the compounds provided herein below (see Schemes 1-8 below).

Amines attached to aryl or heteroaryl ring systems are useful as intermediates in the preparation of the compounds provided herein. There are a number of methods for preparing such intermediates known to those skilled in the art of organic chemistry. Several methods of preparing amines useful for preparing the compounds provided herein are illustrated in Schemes 1-7.

Substituted aniline of Form II useful herein is prepared from commercially available 3-amino-4-methylbenzoic acid as shown in Scheme 1 using methods similar to those disclosed in International Patent Application Publication No. WO 02/40486. can do. Aniline is protected by the Boc group. This is then condensed with methylamine using coupling agents EDC and HOBt. The Boc group is then removed with HCl in dioxane to afford the desired substituted aniline of type II as a hydrochloride salt.

Substituted anilines of type III useful herein can be prepared from commercially available 3-amino-4-methylbenzoic acid as shown in Scheme 2. Aniline of type III is obtained by condensation with cyclopropylamine using the coupling agent EDC.

Substituted aniline of type IV useful herein is prepared from commercially available 4-methyl-3-nitrobenzoic acid as shown in Scheme 3 using a method analogous to that disclosed in International Patent Application Publication No. WO 03/033482. can do. Condensation of the acid with t-butoxycarbonylhydrazide using coupling agents HBTU and HOBt yields a protected acyl hydrazide. Deprotection with TFA followed by condensation with triethyl orthoformate yields oxadiazolyl-substituted nitrotoluene. The nitro group is hydrogenated to give the desired aniline of type IV.

Substituted anilines of type V useful herein are described in Han et al. , J. Med. Chem., 41, 2019-2028 (1998), can be prepared from commercially available 4-methyl-3-nitrobenzamide as shown in Scheme 4. The indicated aryl carboxamides are condensed with N, N-dimethylformamide diethyl acetal. It is then reacted with hydrazine in acetic acid to form triazolyl-substituted nitrotoluene. The nitro group is hydrogenated to give the desired aniline of Form V.

Substituted anilines of type VI useful herein can be prepared from commercially available methyl 4-iodobenzoate as shown in Scheme 5. The aromatic precursor is nitrated followed by reduction of the nitro group to yield aniline. Palladium-catalyst coupling with ethynyl dimethylsilane followed by desilylation and saponification affords the desired ethynyl-substituted aminobenzoic acid. Coupling with methoxyamine using the coupling agent EDC yields the desired aniline of Form VI. For example, Eur . J. Org . Chem . , 4607 (2001).

Alternatively, the substituted aniline of Form VI useful herein can be prepared from 4-amino-3-nitrobenzoic acid as shown in Scheme 6. The aryldiazonium salt is iodide substituted and then esterified with methanol to afford methyl 4-iodo-3-nitrobenzoate. The nitro group is reduced with SnCl ₂ to afford the desired aniline. Ethynyltrimethyl-silane and palladium-catalyzed coupling are then desilylated and saponified to yield ethynyl-substituted aminobenzoic acid. Coupling with methoxyamine using the coupling agent EDC yields aniline of type VI. For example, Eur . J. Org . Chem. , 4607 (2001).

As shown in Scheme 7, substituted anilines of type VII useful herein can be prepared from intermediate methyl 4-iodo-3-nitrobenzoate, which can be synthesized as shown in Scheme 6. Palladium catalyst coupling with vinyltributyltin, followed by addition of carbene to the resulting styrene double bond, affords cyclopropyl substituted methyl nitrobenzoate. The nitro group is reduced, followed by Boc protection and saponification to afford protected 3-amino-4-cyclopropylbenzoic acid. Coupling with the alkoxyamine using the coupling agent EDC yields the desired aniline of type VII. See, for example, International Patent Application Publication Nos. WO 02/092087 and WO 02/40486.

Hydrazines attached to aryl or heteroaryl ring systems are useful herein as intermediates. There are a number of methods known to those skilled in the art of organic chemistry for preparing such intermediates. One method of making certain hydrazines useful herein is illustrated in Scheme 8.

Aryl hydrazine of type VIII useful herein can be prepared from 3-amino- N -methoxy-4-methylbenzamide hydrochloride, which can be prepared according to the method disclosed in International Patent Application Publication No. WO 02/40486. An aryldiazonium salt is formed and subsequently reduced with SnCl ₂ to afford the desired hydrazine of type VIII.

In addition, as shown in Scheme 8, aryl hydrazine of type IX useful herein may be prepared from 3-amino- N -cyclopropyl-4-methylbenzamide, which may be prepared according to the method shown in Scheme 2. have. An aryldiazonium salt is formed and subsequently reduced with SnCl ₂ to afford the desired hydrazine of type IX.

Similarly, other hydrazines can also be prepared from amines such as those described in Schemes 1-7 above.

In addition, as shown in Scheme 9, the arylonitrile of Form X useful herein can be prepared from aryl esters and acetonitrile. Acetonitrile is treated with lithium diisopropylamide in THF at −78 ° C., followed by the addition of aryl esters to give the corresponding aryloylacetonitrile. The intermediate is then reacted with N, N'-diphenylformamidine under reflux in a solvent such as toluene to give the desired corresponding acrylonitrile of Form X.

In addition, as shown in Scheme 10, aminopyrazoles of type XI useful herein are acrylonitrile of type X, which may be prepared according to the method shown in Scheme 9, and the method shown in Scheme 8 It can be prepared from hydrazines such as Forms VIII and IX which can be prepared. Acrylonitrile and hydrazine are heated to 60-100 ° C. in a solvent such as DMF or ethanol to afford the desired aminopyrazole of Form XI.

In addition, as shown in Scheme 11, aminopyrazoles of type XIII useful herein treat acrylonitrile of type X prepared according to the method shown in Scheme 9 with sodium hydride and carbon disulfide, followed by It can be prepared from acrylonitrile of Form XII, which can be prepared by treatment with domethane, and hydrazines such as Forms VIII and IX, which can be prepared according to the method shown in Scheme 8. Acrylonitrile and hydrazine are heated to 60-100 ° C. in a solvent such as DMF or ethanol to afford the desired aminopyrazole of Form XIII.

Furthermore, as shown in Scheme 12, aminopyrazoles of Form XIV useful herein can be prepared according to the method shown in Scheme 8, and acrylonitrile of Form XII, which can be prepared according to the method shown in Scheme 11. It can be prepared from hydrazines such as Forms VIII and IX which can be prepared. The intermediate XII is treated with alcohol alkoxide and then heated to 60-100 ° C. with hydrazine in a solvent such as DMF or ethanol to give the desired aminopyrazole of type XIII.

In addition, as shown in Scheme 13, the aminoimidazoles of Form XV useful herein can be prepared from substituted anilines of Form III, which can be prepared according to the method shown in Scheme 2. Aniline is heated in triethyl orthoformate. After removal of the solvent in vacuo, the product is reacted with aminomalononitrile p -toluenesulfonate and sodium acetate in acetic acid to yield aminocyanoimidazole intermediates. The intermediate is reacted with Grignard reagent to give the desired aminoimidazole of Form XV.

Compounds provided herein can be prepared from hydrazines attached to aryl or heteroaryl ring systems using the methods disclosed in US Pat. Nos. 6,316,466, 6,376,527, and 6,444,696.

Additional synthetic methods useful for the synthesis of the compounds provided herein are disclosed below, which disclosures are incorporated herein by reference in their entirety.

1) J. J. Heterocyclic Chem. 17, 631 (1980)]

2) Tetrahedron 55 (48), 13703 (1999)

3) European Patent Number EP 0 713 876

4) Chemische Berichte 126 (10), 2317 (1993)

5) Journal of Organic Chem. 58 (24), 6620 (1993)]

6) Tetrahedron Letters 35, 3239 (1973)

7) Journal of Chemical Research, Synopses 1, 2 (1997)

8) Boletin de la Sociedad Quimica del Peru 53 (3), 150 (1987)

9) Journal of the Chemical Society, Chemical Communications 2, 35 (1973)

10) Comptes Rendus des Seances de l'Academie des Sciences, Series C: Sciences Chimiques 274 (20), 1703 (1972)

Also provided herein are compounds prepared according to the methods disclosed herein.

D. Formulation of Pharmaceutical Compositions

Also provided herein are pharmaceutical compositions comprising a compound provided herein. The composition can be used, for example, as a medicament. The composition may contain, for example, a pharmaceutically acceptable excipient or carrier. The compositions or medicaments provided herein can be used to treat, prevent or alleviate one or more symptoms of a p38 kinase mediated disease or disorder, including inflammatory diseases.

As such, provided herein are pharmaceutical compositions capable of treating p38-kinase-related symptoms including TNF-α, IL-1, and / or IL-8 mediated symptoms as described above. The composition may contain other therapeutic agents as described above, and may be conventional solid or liquid vehicles or diluents, and pharmaceutical additives of the type appropriate for the desired mode of administration, such as excipients, binders, according to techniques well known in the pharmaceutical formulation art. , Preservatives, stabilizers, flavors, and the like).

The compounds provided herein can be administered by any means suitable for the condition to be treated, which may vary depending on the need for site-specific treatment or the amount of drug to be delivered. Topical administration is generally useful for skin-related diseases, and systemic treatment is generally useful for cancer or pre-cancer symptoms, but other modes of delivery are contemplated. Orally (eg in the form of a liquid formulation including tablets, capsules, granules, powders, or syrups); Topically (eg in the form of a liquid, suspension, gel or ointment); Sublingually; Buccally; Parenterally (eg, by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (eg, sterile injectable aqueous or non-aqueous solutions or suspensions)); Nasal (eg by inhalation spray); Topically (eg in the form of a cream or ointment); Rectally (eg in the form of suppositories); Or the compound may be delivered in liposomes. Unit dosage formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compound may be administered in a form suitable for immediate release or sustained release. Immediate release or sustained release is achieved with suitable pharmaceutical compositions, especially in the case of sustained release, with devices such as subcutaneous implants or osmotic pumps. Exemplary compositions for topical administration include topical carriers such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include, for example, microcrystalline cellulose to provide bulk, alginic acid or sodium alginate as suspending agent, methylcellulose as viscosity enhancer and sweeteners or flavoring agents known in the art. ; And as soon as it can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art. Release tablets. The compounds of the invention may also be delivered orally by sublingual and / or buccal administration in molded, compressed or freeze-dried tablets. Exemplary compositions may include rapid dissolution diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. In addition, high molecular weight excipients such as cellulose (AVICEL®) or polyethylene glycol (PEG); excipients that aid in mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxy Methyl cellulose (SCMC), and / or maleic anhydride copolymers (eg GANTREZ®); and release modifiers, such as polyacrylic acid copolymers (eg CARBOPOL 934 ( ®) may be included in the formulation, and lubricants, glidants, flavors, colorants and stabilizers can be added to facilitate manufacture and use.

Exemplary compositions for nasal aerosol or inhalation administration include, for example, benzyl alcohol or other suitable preservatives, absorption accelerators that enhance absorption and / or bioavailability, and / or other solubilizers or dispersants known in the art. Liquid solutions that may be contained.

Exemplary compositions for parenteral administration include, for example, suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or Injectable solutions or suspensions which may contain other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides and fatty acids (including oleic acid).

Exemplary compositions for rectal administration include, for example, suppositories which may contain suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters or polyethylene glycols (which are liquefied in solid or rectal cavity at normal temperatures) and / or Dissolved to release the drug).

An effective amount of a compound provided herein can be determined by one skilled in the art, and for mammals exemplary dosages comprise from 0.05 to 100 mg of active compound per kg of body weight per day, which is in single or separate divided dosage forms, For example, 1 to 4 times a day. The specific dosage level and frequency of administration for any particular subject varies and includes the activity of the specific compound to be used, the metabolic stability and duration of action of the compound, the species of the subject, age, weight, general health, sex and diet, administration It will be understood that this will vary depending on various factors, including manner and duration, rate of release, drug combination, and severity of the particular symptom. Subjects to be treated include animals, generally mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. As such, when the term “patient” is used herein, it is to be understood that the term encompasses all subjects, particularly humans, including mammalian species, which are affected by the mediation of the p38 enzyme level.

In one embodiment, provided herein is a method of making a medicament comprising combining a compound provided herein with a pharmaceutically acceptable excipient and making the mixture in the form of a herbal formulation.

E. How to Use Compounds and Compositions

In further embodiments, compounds provided herein can be used to treat, prevent or alleviate one or more symptoms of an inflammatory disease. The compounds provided herein can be used for the manufacture of a medicament for the treatment or prophylaxis of an inflammatory disease in another embodiment.

Compounds provided herein are p38 kinase activity, and in particular, screening inhibitors of homologues p38α and p38β. Thus, the compounds provided herein are useful for treating symptoms associated with p38 kinase activity. Such symptoms include diseases in which cytokine levels are mediated as a result of intracellular signaling through p38, and in particular those associated with the overproduction of cytokines IL-1, IL-4, IL-8, and TNF-α. Provided herein are methods of treating a disease by administering a compound provided herein that inhibits p38 activity. Also provided herein are methods of inhibiting or delaying the onset of a disease or disorder by administering a compound provided herein. The methods provided herein can be used to completely or partially reduce a symptom or disease state of a disease, and to alleviate, alleviate, or reduce a disease or disorder and / or symptoms thereof. When referring to the inhibition of “p-38α / β kinase” herein it is meant to inhibit either p38α and / or p38β. As such, when referring to an IC ₅₀ value for inhibiting p-38α / β kinase, this means that the compound has the effect of inhibiting at least one or both of p38α and p38β kinase.

In view of their activity as inhibitors of p38α / β kinases, the compounds provided herein provide for inflammatory diseases, autoimmune diseases, disruptive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases. It is useful for treating p-38 related symptoms, including but not limited to.

More specifically, specific symptoms or diseases that can be treated with the compounds of the present invention include pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus , Scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease , Ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, inflammatory reactions induced by endotoxins, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter syndrome, gout Traumatic arthritis, rubella arthritis, acute synovitis, pancreatic β-cell disease; Diseases characterized by huge neutrophil infiltration; Rheumatoid spondylitis, gouty arthritis and other arthritis symptoms, brain malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever and myalgia from infection, cachexia attached to infection, melo Meloid formation, scar tissue formation, ulcerative colitis, paralysis, influenza, osteoporosis, osteoarthritis and multiple myeloma-related bone disorders, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, Sepsis, septic shock and Shigellosis; Neurodegenerative diseases caused by Alzheimer's disease, Parkinson's disease, cerebral ischemia or traumatic injury; Angiogenic disorders, including solid tumors, ocular angiogenesis and infantile hemangiomas; Viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, SARS, ARC or malignant tumors and herpes; Stroke, myocardial ischemia, ischemia during stroke heart attack, long-term hypoxia, vascular hyperplasia, mental and reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome and prostaglandin endoperoxidase synthase Including but not limited to symptoms associated with the second-2.

In addition, the p38 inhibitors provided herein inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin endopeperoxide synthase-2 (PGHS-2) (also referred to as cyclooxygenase-2; COX-2). do. Thus, additional p38-related symptoms include edema, analgesia, fever and pain such as neuromuscular pain, headache, pain caused by cancer, toothache and arthritis pain. Compounds of the invention also include veterinary viral infections, such as but not limited to lentiviral infections, including but not limited to equine infectious anemia virus; Or retroviral infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus. When the term “p38-related symptoms” or “p38-related diseases or disorders” are used herein, each of them is affected by p38 kinase activity as well as all the symptoms identified above, even if repeated over a period of time. It should be understood to include other symptoms.

As such, provided herein are methods for treating such symptoms comprising administering an effective amount of one or more compounds provided herein or a pharmaceutically acceptable derivative thereof in a subject in need thereof. Methods of treating p38 kinase-related symptoms include administering the compounds provided herein, alone or in combination with each other, and / or in combination with therapeutic agents useful for treating the symptoms. Examples of such other therapeutic agents are described in US Pat. No. 4,200,750 and S. Ceccarelli et al. (1998) European Journal of Medicinal Chemistry 33 : 943-955; corticosteroids, rolipram, calfostine, CSAID, 4-substituted imidazo [1,2-A] quinoxaline; Interleukin-10, glucocorticoids, salicylates, nitrates, and other immunosuppressive agents; Nuclear translocation inhibitors such as deoxyspergualin (DSG); Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; Steroids such as prednisone or dexamethasone; Antiviral agents, such as Abakavir; Antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); Cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-α inhibitors such as tenipap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (Syrrolimus or Rapamune or derivatives thereof).

Such other therapeutic agents in combination with the compounds provided herein can be used, for example, in amounts as indicated in the US Physicians' Desk Reference (PDR) or in amounts determined by one of ordinary skill in the art. In the methods provided herein, these other therapeutic agent (s) may be administered before, simultaneously with, and after the compound of the present invention.

The following examples illustrate the embodiments herein and are to be understood as not limiting the scope of the claims. Abbreviations used in the examples are defined below. The compounds of the Examples are identified by the Examples and Steps in which they are prepared (e.g., "1A" refers to the compounds of Step A of Example 1), or when the title compounds of the Examples are Examples (Examples) For example, “2” refers to the title compound of Example 2).

Abbreviation

Ph = phenyl

Bz = benzyl

t-Bu = tertiary butyl

Me = methyl

Et = ethyl

Pr = profile

Iso-P or i-Pr = Isopropyl

MeOH = Methanol

EtOH = ethanol

EtOAc = ethyl acetate

Boc = tert-butyloxycarbonyl

CBZ = carbenzyloxy or carbenzoxy or benzyloxycarbonyl

DCM or CH ₂ Cl ₂ = Dichloromethane

DCE = 1,2-dichloroethane

DMF = Dimethyl Formamide

DMSO = dimethyl sulfoxide

TFA = trifluoroacetic acid

THF = tetrahydrofuran

HATU = O- (7-azabenzotriazol-1-yl- N, N, N ', N'- tetramethyluronium hexafluorophosphate

KOH = potassium hydroxide

K ₂ CO ₃ = potassium carbonate

POCl ₃ = Phosphorus oxychloride

KOtBu = potassium t-butoxide

EDC or EDCI = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

DIPEA = diisopropylethylamine

HOBt = 1-hydroxybenzotriazole hydrate

m-CPBA = m-chloroperbenzoic acid

NaH = sodium hydride

NaOH = sodium hydroxide

Na ₂ S ₂ O ₃ = sodium thiosulfate

Na ₂ SO ₄ = sodium sulfate

Pd = palladium

Pd / C = palladium on carbon

min = minutes

L = liter

mL = milliliters

μL = microliters

g = grams

mg = milligrams

mol = mol

mmol = millimoles

meq = milliequivalents

RT or rt = room temperature

ret. t. Or t _R = HPLC retention time (minutes)

sat or sat'd = saturation

Common way. Mass spectrometry data were obtained on a Thermo Finnigan LCQ Duo Ion Trap mass spectrometer. In the examples, "HPLC (6-minute gradient) is a Keystone C18 Beta Basic column, 0.4 mL / min flow rate, 6-minute linear gradient elution (starting solvent% B = 0; final solvent% B = 100) , Solvent A: acetonitrile + 0.025% TFA; solvent B = H ₂ O + 0.025% TFA. "HPLC (4-minute gradient) Keystone C18 beta basic column, 0.5 mL / min flow rate, 4-minute linear gradient elution (departure) Solvent% B = 0, final solvent% B = 100), solvent A: acetonitrile + 0.025% TFA; Solvent B = H ₂ O + 0.025% TFA.

Example  One

3- [5-amino-4- (3- Iodo - Benzoyl ) -Pyrazol-1-yl] -N- Methoxy -4- methyl - Benzamide  Produce

A. 3- Hydrazino -N- Methoxy -4- methyl - Benzamide

Of 3-amino-N-methoxy-4-methyl-benzamide 1 (102 mg, 0.56 mmol, in International Patent Application Publication No. WO 02/40486 A2, pg. 66) in water (5 ml) at 0 ° C. To the stirred solution was added concentrated HCl (5 mL) followed by sodium nitrite (43 mg, 0.62 mmol). The reaction mixture is stirred at 0 ° C. for 40 minutes, then a solution of tin (II) chloride (241 mg, 1.27 mmol) in concentrated HCl (1 mL) is added, and the mixture is stirred for 1 hour and then −20 ° C. After standing for 20 hours at it was warmed to room temperature and concentrated to a white solid. The solid was triturated with ethanol, the solid was filtered, the filtrate was concentrated to give 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (486 mg) with a tin salt and ethanol (white solid ), Which was used without further purification. HPLC (6 min gradient) t _R 0.78 min; MS m / z 195.9 [M + H] ⁺ .

B. 3- [5-amino-4- (3- Iodo - Benzoyl ) - Pyrazole -1-yl] -N- Methoxy -4- methyl - Benzamide

To a stirred solution of 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (116 mg, estimated 0.14 mmol) in EtOH (10 ml) 2- (3-iodo-benzoyl) -3-phenyl Amino-acrylonitrile 3 (59 mg, 0.14 mmol, Preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84) is added and the mixture is heated for 4 hours (bath temperature = 65-70 ° C.) , Additional 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (80 mg, 0.11 mmol) was added and the mixture was heated at the same temperature for 27 hours. It was cooled to rt, concentrated, redissolved in EtOAc, then it was washed with water and brine, dried over Na ₂ S0 ₄ and concentrated to give a crude semisolid. The mixture is then purified by flash chromatography, eluting with 1: 1 EtOAc / hexanes to remove impurities followed by 100% EtOAc, thereby removing 3- [5-amino-4- (3-iodo-benzoyl) -pyrazole-1 -Yl] -N-methoxy-4-methyl-benzamide 4 (38 mg, 0.08 mmol, 55%) was obtained as off-white solid. HPLC (6 min gradient) t _R 3.49 min;

Example  2

3- (5-amino-4- Benzoyl - Pyrazole -1-yl) -N- Methoxy -4- methyl - Benzamide  Produce

To a stirred solution of 3-amino-N-methoxy-4-methyl-benzamide 1 (104 mg, 0.58 mmol) in water (2 ml) at 0 ° C. was concentrated HCl (2 mL) followed by sodium nitrite (44 mg , 0.63 mmol) was added. The reaction mixture is stirred at 0 ° C. for 40 minutes, then a solution of tin (II) chloride (245 mg, 1.30 mmol) in concentrated HCl (1 mL) is added and the mixture is stirred for 40 minutes and then −20 ° C. After standing for 20 hours at it was warmed to room temperature and concentrated to a white solid. The solid was triturated with ethanol, the solid was removed and 2-benzoyl-3-phenylamino-acrylonitrile 5 (144 mg, 0.58 mmol, Preparation: Grothaus, J. Am. Chem. Soc. 58, 1334 (1936)]) and the mixture was heated for 16 h (bath temperature = 65-70 ° C.). The mixture was cooled to room temperature, concentrated and purified by flash chromatography eluting with 1: 1 EtOAc / hexanes to remove impurities followed by 100% EtOAc to remove 3- (5-amino-4-benzoyl-pyrazole-1- Ill-N-methoxy-4-methyl-benzamide 6 (41 mg, 0.12 mmol, 28%) was obtained as off-white solid. HPLC (4-minute gradient) t _R 1.93 min;

Example  3

3- (5-amino-4- Benzoyl - Pyrazole -1-yl) -4- methyl Preparation of benzoic acid

A. 3-hydrazino-4- methyl -Benzoic acid Hydrochloride

To a stirred solution of 3-amino-4-methylbenzoic acid 1 (5.64 g, 31.2 mmol, 1.0 equiv) in 100 mL dioxane and 100 mL water at 0 ° C. add 100 mL of concentrated HCl, followed by sodium nitrite (2.82 g , 40.9 mmol, 1.1 equiv) was added as a solid in fractions at a rate that controls gas evolution and foam formation for 45 minutes. A clear brown solution was produced. Anhydrous tin (II) chloride (15.62 g, 83.7 mmol, 2.25 equiv) was dissolved in concentrated HCl (25 mL) and added dropwise at 0 ° C. over 25 mL. After 1 hour, the precipitate was filtered off, washed with dioxane and then dried under vacuum to afford 3-hydrazino-4-methyl-benzoic acid hydrochloride 2 (4.98 g, 66%) as a tan solid: HPLC (4 Min gradient) t _R 0.97 min;

B. 3- (5-amino-4- Benzoyl -Pyrazol-1-yl) -4- methyl -Benzoic acid

To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride 2 (242 mg, 1.19 mmol, 1.0 equiv) in 25 mL of ethanol 2-benzoyl-3-phenylamino-acrylonitrile 4 (296 mg, 1.19 mmol, 1.0 equiv, Preparation: Grothasu, Davis, J. Am. Chem . Soc. , 58 , 1334 (1936)) and triethylamine (161 μL, 1.19 mmol, 1.0 equiv) were added and the mixture was Heated to 65 ° C. When the temperature reached 65 ° C., all solids dissolved. After 3 hours, LC-MS indicated hydrazine was consumed. The solid was filtered to give 3- (5-amino-4-benzoyl-pyrazol-1-yl) -4-methyl-benzoic acid 5 (95 mg, 25%) as a beige solid: HPLC (4-minute gradient) ) t _R 2.10 min;

Example  4

3- (5-amino-4- Benzoyl - Pyrazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide  Produce

To a stirred solution of 3- (5-amino-4-benzoyl-pyrazol-1-yl) -4-methyl-benzoic acid 5 (Example 3, 700 mg, 2.18 mmol, 1.0 equiv) in 30 mL of DMF was added EDCI ( 855 mg, 4.35 mmol, 2.0 equiv), HOBt (589 mg, 4.35 mmol, 2.0 equiv) and diisopropylethylamine (1.59 mL, 8.71 mmol, 4.0 equiv) were added and the solution was stirred at rt for 15 min and , Cyclopropylamine (302 μL, 4.35 mmol, 2.0 equiv) was added and the reaction stirred for 1 h. The mixture was diluted with EtOAc (300 mL), washed with water (2 × 25 mL) and brine (25 mL), dried (Na ₂ SO ₄ ) and concentrated. The product was purified by flash chromatography on silica gel eluting with 8/2 EtOAc / MeOH to afford the product as a brown oil. The product was further purified by trituration with 1/1/1 EtOAc / hexanes / CH ₂ Cl ₂ and dried under vacuum to afford 3- (5-amino-4-benzoyl-pyrazol-1-yl) -N-cyclo. Propyl-4-methyl-benzamide 6 (387 mg, 50%) was obtained as a white powder: HPLC (4 min gradient) t _R 2.11 min;

Example  5

3- [5-amino-4- (3- Iodo - Benzoyl ) - Pyrazole -1-yl] -4- methyl Preparation of benzoic acid

2- (3-iodo-benzoyl) in a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride 1 (Example 3A, 314 mg, 1.54 mmol, 1.0 equiv) in 50 mL of ethanol and 5 mL of methanol 3-phenylamino-acrylonitrile 2 (579 mg, 1.54 mmol, Preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84) was added. The mixture was heated to 75 ° C for 18 h. The precipitated solid was collected on a fritted filter and washed with ethanol to afford 3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -4-methyl-benzoic acid 3 ( 153 mg, 22%) was obtained as a white solid.

Example  6

3- [5-amino-4- (3- Iodo - Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide  Produce

A. 3- (N'- tert - Butoxycarbonyl -Hydrazino) -4- methyl -Benzoic acid

3-hydrazino-4-methyl-benzoic acid hydrochloride 1 (Example 3A, 13 g, 64.5 mmol) was dissolved in dioxane (200 mL) and H ₂ O (100 mL). Aqueous NaOH (5.16 g NaOH in 100 mL H ₂ O, 2 × 64.5 mmol) was added followed by the addition of (Boc) ₂ O (15.5 g, 1.1 × 64.5 mmol) immediately. The reaction mixture was stirred at room temperature for 2 hours. Concentrated on a rotary evaporator. Then H ₂ O and CH ₂ Cl ₂ (some MeOH) were added. Strongly acidic H ⁺ resin was added with stirring to neutralize the mixture to pH <2. It was filtered and the resin was washed with CH ₂ Cl ₂ and MeOH. The aqueous layer was washed twice with CH ₂ Cl ₂ (with some MeOH added). The combined organic layers were dried over Na ₂ S0 ₄ (add some EtOAc). Filtration and concentration gave 3- (N'-tert-butoxycarbonyl-hydrazino) -4-methyl-benzoic acid 4 (16 g, 94%) as a white solid.

B. N '-(5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) - Hydrazinecarboxylic acid tert - butyl ester

3- (N'-tert-butoxycarbonyl-hydrazino) -4-methyl-benzoic acid 4 (14 g, 52.6 mmol) was dissolved in DMF (250 mL). EDCI (20 g, 105.2 mmol) and HOBt (16 g, 105.2 mmol) were added. The mixture was stirred at rt for 30 min. Cyclopropylamine (7.4 mL, 105.2 mmol) was added followed by DIPEA (37 mL, 4 × 52.6 mmol). The reaction mixture was stirred at rt for 18 h. After the reaction mixture was concentrated in vacuo, H ₂ O was added. The mixture was then extracted three times with CH ₂ Cl ₂ . The organic layer was washed with aqueous NaCl solution. Dry over Na ₂ SO ₄ , filter and concentrate to give a white solid. The crude product was dissolved in CH ₂ Cl ₂ / MeOH and then purified by silica gel column chromatography (CH ₂ Cl ₂ / EtOAc, gradient 2/1 to 1/1) to afford the desired product. The product was further purified by recrystallization from EtOAc / CH ₂ Cl ₂ and the collected solids were washed with EtOAc to yield N '-(5-cyclopropylcarbamoyl-2-methyl-phenyl) -hydrazinecarboxylic acid tert-butyl Ester 5 (11 g, 69%) was obtained.

C. N- Cyclopropyl -3-hydrazino-4- methyl - Benzamide , Trifluoroacetic acid  salt

N '-(5-cyclopropylcarbamoyl-2-methyl-phenyl) -hydrazinecarboxylic acid tert-butyl ester 5 It was dissolved in CH ₂ Cl ₂ / TFA (2/1) containing 2% H ₂ O and the mixture was stirred at rt for 3 h. Concentration in vacuo afforded a syrup. CH ₂ Cl ₂ and toluene were added and concentrated again under vacuum to afford N-cyclopropyl-3-hydrazino-4-methyl-benzamide, trifluoroacetic acid salt 6 as off-white solid. (Yield: 100%)

D. 3- [5-amino-4- (3- Iodo - Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide

To a stirred solution of N-cyclopropyl-3-hydrazino-4-methyl-benzamide, trifluoroacetic acid salt 6 (648 mg, 1.74 mmol, 1.0 equiv.) In 2 mL of ethanol, 2- (3-iodo- Benzoyl) -3-phenylamino-acrylonitrile 2 (550 mg, 1.74 mmol, Preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84) and DIEA (0.50 mL, 2.9 mmol) were added. The mixture was heated to 160 ° C. for 40 minutes using microwave. The mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc / hexanes, gradient 1/1 to 2/1) to afford 3- [5-amino-4- (3- iodo-benzoyl) -pyrazol-1-yl ] -N-cyclopropyl-4-methyl-benzamide 7 (589 mg, 70%) was obtained as a white solid.

Example  7

{5-amino-1- [2- methyl -5- (4H- [1,2,4] Triazole -3 days)- Phenyl ] -1H- Pyrazole -4-yl}-Preparation of Phenyl-Methanone

A. N- Dimethylaminomethylene -4- methyl 3-nitro- Benzamide

4-Methyl-3-nitro-benzamide 1 (10 g, 56 mmol) was suspended in 80 mL of N, N-dimethylformamide dimethylacetal and then heated to 95 ° C for 2 h. The red solution was cooled to room temperature with stirring. After an additional 2 hours, the resulting red precipitate was collected on a frit filter and washed three times with Et ₂ O to render N-dimethylaminomethylene-4-methyl-3-nitro-benzamide 2 (8.7 g, 66%) red. Obtained as a solid. HPLC (4 min gradient) t _R 1.76 min; MS m / z 236.0 [M + H] ⁺ .

B. 3- (4- methyl 3-nitro- Phenyl ) -4H- [1,2,4] Triazole

Anhydrous hydrazine (4.7 mL, 180 mL) was added dropwise to a solution of N-dimethylaminomethylene-4-methyl-3-nitro-benzamide 2 (8.6 g, 37 mmol) in 250 mL of acetic acid. The bright orange solution was heated at 95 ° C. for 1.5 h and then cooled and stirred at rt for 18 h. Acetic acid was removed under vacuum and the residue partitioned between H ₂ O and EtOAc. The organic layer was washed twice with saturated NaHCO ₃ solution and then dried over MgSO ₄ . After filtration and concentration in vacuo, the residue was triturated with warm EtOAc and the resulting off-white solid collected on a frit filter to give 3- (4-methyl-3-nitro-phenyl) -4H- [1,2, 4] Triazole 3 (5.8 g, 77%) was collected. HPLC (4-minute gradient) t _R 1.82 min;

C. 2- methyl -5- (4H- [1,2,4] Triazole -3 days)- Phenylamine

3- (4-methyl-3-nitro-phenyl) -4H- [1,2,4] triazole 3 (5.75 g, 28.2 mmol) in 220 mL of ethanol containing 2.35 mL (about 28.2 mmol) of concentrated aqueous HCl. Was suspended. Under nitrogen, 900 mg of 10% palladium (anhydrous) on activated carbon was carefully added. Hydrogen gas was bubbled through the reaction mixture via a balloon attached to a syringe needle for 5 minutes. The reaction mixture was then stirred at room temperature for 5 hours under a hydrogen gas atmosphere maintained by a balloon. The catalyst was removed by filtration through a short pad of Celite. The filtrate was concentrated in vacuo and the residue was neutralized with saturated NaHCO ₃ solution. The mixture was extracted six times with EtOAc and the combined organic layers were dried over MgSO ₄ . After filtration and concentration in vacuo, the residue was recrystallized in EtOAc to give 2-methyl-5- (4H- [1,2,4] triazol-3-yl) -phenylamine 4 (4.5 g, 92%) Was obtained as an off-white solid. HPLC (4-minute gradient) t _R 0.79 min;

D. [2- methyl -5- (4H- [1,2,4] Triazole -3 days)- Phenyl ] -Hydrazine

2-methyl-5- (4H- [1,2,4] triazol-3-yl) -phenylamine 4 (200 mg, 1.15 mmol, in dioxane (5 ml) and water (5 ml) at 0 ° C. Prepared), followed by concentrated HCl (10 mL) followed by sodium nitrite (87 mg, 1.26 mmol). The reaction mixture was stirred at 0 ° C. for 40 minutes, and then tin (II) chloride (481 mg, 2.59 mmol) in concentrated HCl (1 mL) was added dropwise. The mixture was stirred at 0 ° C. for 2 hours, forming a white solid precipitate. The solid was collected by filtration and identified [2-methyl-5- (4H- [1,2,4] triazol-3-yl) -phenyl] -hydrazine 5 (261 mg) and used without further purification. . HPLC (4 min gradient) t _R 0.71 min; MS m / z 190.1 [M + H] ⁺ .

E. {5-amino-1- [2- methyl -5- (4H- [1,2,4] Triazole -3 days)- Phenyl ] -1H-pyrazol-4-yl- Phenyl -Metanon

To a stirred solution of [2-methyl-5- (4H- [1,2,4] triazol-3-yl) -phenyl] -hydrazine 5 (261 mg, estimated 1.15 mmol) in EtOH (25 ml) 2 -Benzoyl-3-phenylamino-acrylonitrile 6 (285 mg, 1.15 mmol, Preparation: Grothaus, J. Am. Chem. Soc. 58, 1334 (1936)) is added and the mixture is 65-70. Heated to C for 12-16 h. It was cooled to room temperature and concentrated to give crude product. The mixture was then purified by flash chromatography eluting with 1: 1 EtOAc / hexanes to afford {5-amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl). -Phenyl] -1 H-pyrazol-4-yl} -phenyl-methanone 7 (21 mg, 0.09 mmol, 8%) was obtained as a white solid. HPLC (4-minute gradient) t _R 1.89 min;

Example  8

3- [5-amino-4- (3- [1,3] Dioxolane -2 days- Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

A. 3- [1,3] Dioxolane 2-yl-benzoic acid methyl  ester

A mixture of 3-formyl-benzoic acid methyl ester 1 (6.09 g, 37.2 mmol), ethylene glycol (2.28 mL, 40.9 mmol) and p -toluenesulfonic acid monohydrate (0.78 g, 4.09 mmol) was added to Dean-Stark. Stark) was refluxed overnight with a device. TLC plates showed that all starting material was gone. The reaction mixture was poured into a mixture of cooled aqueous NaHCO ₃ and EtOAc. The organic layer was separated and dried over Na ₂ SO ₄ . Filtration and concentration gave the crude product, which was purified by silica gel chromatography (eluent: 8/1 hexanes / ethyl acetate). The desired 3- [1,3] dioxolan-2-yl-benzoic acid methyl ester 2 (6.41 g, 83%) was obtained as a colorless oil.

B. 3- (3- [1,3] Dioxolane -2 days- Phenyl ) -3-oxo-propionitrile

To a mixture of acetonitrile (1.90 mL, 36.4 mmol) in THF (60 mL) was added LDA (1.8 M in THF, 33.9 mL) at -78 ° C. After the mixture was stirred at −78 ° C. for 20 minutes, 3- [1,3] dioxolan-2-yl-benzoic acid methyl ester 2 (6.06 g, 29.1 mmol) in THF (20 ml) was added in one portion. The mixture was stirred at -78 ° C for 1.5 h, then warmed to 0 ° C and stirred at this temperature for 1 h. The reaction was quenched by addition of saturated NH ₄ Cl. The mixture was extracted three times with EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ . Filtration and concentration in vacuo gave a residue, which was purified by silica gel chromatography (CH ₂ Cl ₂ , then 20/1 CH ₂ Cl ₂ / ethyl acetate). The desired 3- (3- [1,3] dioxolan-2-yl-phenyl) -3-oxo-propionitrile 3 (5.71 g, 96%) was obtained as a white solid.

C. 2- (3- [1,3] Dioxolane -2 days- Benzoyl ) -3- Phenylamino Acrylonitrile

3- (3- [1,3] dioxolan-2-yl-phenyl) -3-oxo-propionitrile 3 (3.07 g, 15.0 mmol) and to N, N' -diphenylformamidine (4.10) in toluene g, 21 mmol) was heated to reflux for 18 hours. Concentration in vacuo gave a residue, which was purified by silica gel chromatography (hexane / EtOAc, gradient 3/1 to 2/1, then 1/1). The desired 2- (3- [1,3] dioxolan-2-yl-benzoyl) -3-phenylamino-acrylonitrile 4 (3.88 g, 81%) was obtained as a yellow solid.

D. 3- [5-amino-4- (3- [1,3] Dioxolane -2 days- Benzoyl ) -Pyrazol-1-yl] -N- Cyclopropyl -4- methyl - Benzamide

2- (3- [1,3] dioxolan-2-yl-benzoyl) -3-phenylamino-acrylonitrile 4 (0.20 g, 0.62 mmol) in DMF (3 mL), N-cyclopropyl-3- A mixture of hydrazino-4-methyl-benzamide, trifluoroacetic acid salt 8 (Example 6C, 0.20 g, 0.62 mmol) and DIEA (0.5 mL) was heated to 160 ° C. for 40 minutes using microwave. The mixture was then cooled to rt and concentrated. The obtained residue was purified by silica gel chromatography (gradient 1/4 hexanes / EtOAc to 100% EtOAc). Desired 3- [5-amino-4- (3- [1,3] dioxolan-2-yl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide 5 ( 0.26 g, 100%) was obtained as an orange solid.

Example  9

3- [5-amino-4- (3- Formyl - Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide  Produce

3- [5-Amino-4- (3- [1,3] dioxolan-2-yl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide 5 (Example 8, 1.14 g, 2.6 mmol) was suspended in aqueous AcOH (10 mL, 1.5 M in H ₂ O). Glacial acetic acid was added dropwise until the solution became clear. The reaction mixture was stirred at rt overnight. The solvent was evaporated under reduced pressure to give a residue. Toluene and EtOAc were added and the mixture was concentrated again to give the crude product, which could be purified by silica gel chromatography (hexane / EtOAc: 1/4). Desired 3- [5-amino-4- (3-formyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide 6 (0.91 g, 89%) was yellow foam. Obtained as a mold solid.

Example  10

3- [5-amino-4- (3- Hydroxymethyl - Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl -4- methyl Preparation of Benzamide

3- [5-Amino-4- (3-formyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide 6 (38 mg, 0.098 mmol) in methanol (3 mL) ) Was added NaBH ₄ (11 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by addition of aqueous NaOH and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and saturated NaCl solution. The organics were then dried over Na ₂ SO ₄ , filtered and concentrated to give a residue, which could be purified by silica gel chromatography (eluent: 1/4 hexanes / EtOAc). Desired 3- [5-Amino-4- (3-hydroxymethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide 7 (22 mg, 58%) Obtained as a solid.

Example  11

3- {5-amino-4- [3- (4- methyl Piperazine-1- Yl methyl ) - Benzoyl ]- Pyrazole -1-yl} -N- Cyclopropyl Preparation of 4-methyl-benzamide

Equal doses of 3- [5-amino-4- (3-formyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide in 1,2-dichloroethane and dichloromethane AcOH (0.96 equiv) was added to a mixture of 6 (Example 9, 1.0 equiv) and 1-methyl-piperazine (1.09 equiv). Sodium triacetoxyborohydride (1.5 equiv) was then added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of aqueous NaOH and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and saturated NaCl solution. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated to give a residue, which was silica gel chromatography (eluent: 9/1 CH ₂ Cl ₂ / methanol, then 9/1 / 0.05 CH ₂ Cl ₂ / MeOH / NH ₃ H ₂ O). Yield 67%.

Example  12

3- [5-amino-4- (3-morpholine-4- Yl methyl - Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

Prepared using a procedure similar to Example 11 except that morpholine was used instead of 1-methyl-piperidine. Yield 45%.

Example  13

3- {5-amino-4- [3- (2-morpholin-4-yl- Ethoxy ) - Benzoyl ]- Pyrazole -1-yl} -N- Cyclopropyl Preparation of 4-methyl-benzamide

A. 3- (2- Morpholine Yl- Ethoxy ) -Benzoic acid ethyl ester

Potassium carbonate (6.2 g, 45 mmol) was diluted with ethyl 3-hydroxybenzoate 1 (3.32 g, 20 mmol), 4- (2-chloroethyl) -morpholine hydrochloride (5.58 g, 30 mmol) and 18-crown -6 (20 mg) in DMF solution (100 mL). The mixture was stirred at 100 ° C for 20 h. The solvent was removed in vacuo and the residue suspended in ethyl acetate. The organic layer was washed with saturated NaHCO ₃ solution and then brine and dried over sodium sulfate. The solvent was evaporated to afford the product 3- (2-morpholin-4-yl-ethoxy) -benzoic acid ethyl ester 2 (5.3 g, 95%). Obtained as a pale yellow oil. HPLC (4-minute gradient) t _R 1.47 min; MS m / z 280.2 [M + H] ⁺ .

B. 3- [3- (2- Morpholine Yl- Ethoxy ) - Phenyl ] -3-oxo-propionitrile

Lithium diisopropylamide (16.4 mL, 29.6 mmol, 1.8M solution in heptane / tetrahydrofuran / ethyl benzene) was acetonitrile (1.2 g, 29.6 mmol in anhydrous tetrahydrofuran (20 mL) at -78 ° C. under nitrogen atmosphere. Dropwise). After stirring the reaction mixture for 30 minutes, 3- (2-morpholin-4-yl-ethoxy) -benzoic acid ethyl ester 2 (5.5 g, 19.7 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise, Stir at -78 ° C for 1 h. Water was added, the aqueous layer was separated and acidified to pH 7 with dilute hydrochloric acid. The product was extracted with ethyl acetate. The organic layer was washed with brine and then dried over sodium sulfate. The solvent was removed under vacuum to afford 3- [3- (2-morpholin-4-yl-ethoxy) -phenyl] -3-oxo-propionitrile 3 (4.8 g) as a pale yellow oil. Obtained. HPLC (4 min gradient) t _R 1.11 min; MS m / z 275.2 [M + H] ⁺ .

C. 2- [3- (2- Morpholine Yl- Ethoxy ) - Benzoyl ] -3- Phenylamino Acrylonitrile

3- [3- (2-morpholin-4-yl-ethoxy) -phenyl] -3-oxo-propionitrile 3 (4.8 g, 17.5 mmol) and N, N-di in anhydrous toluene (100 mL) A mixture of phenylformamidine (1.2 g, 24.5 mmol) was heated at 110 ° C. for 3 hours under a nitrogen atmosphere. The solvent was removed and the oily residue was subjected to silica gel column chromatography (gradient 100% EtOAc in 100/10/1 EtOAc / MeOH / Et ₃ N) to give 2- [3- (2-morpholin-4-yl- Ethoxy) -benzoyl] -3-phenylamino-acrylonitrile 4 (3.1 g, 47%) Obtained as a pale yellow solid. HPLC (4-minute gradient) t _R 2.04 min; MS m / z 378.2 [M + H] ⁺ .

D. 3- {5-amino-4- [3- (2- Morpholine Yl- Ethoxy ) - Benzoyl ] -Pyrazol-1-yl} -4-  methyl -Benzoic acid

2- [3- (2-Morpholin-4-yl-ethoxy) -benzoyl] -3-phenylamino-acrylonitrile 4 (189 mg, 0.5 mmol) and 3-hydrazino-4-methyl-benzoic acid hydro Chloride 7 (Example 3A, 152 mg, 0.75 mmol) was suspended in N, N-dimethylformamide (5 mL) and heated at 160 ° C. for 30 minutes using microwave. The solvent was evaporated and the residue was subjected to column chromatography (EtOAc-MeOH). Pale yellow to the product 3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) -benzoyl] -pyrazol-1-yl} -4-methyl-benzoic acid 5 (200 mg) Obtained as a solid. HPLC (4 min gradient) t _R 1.60 min; MS m / z 451.2 [M + H] ⁺ .

E. 3- {5-amino-4- [3- (2-morpholin-4-yl- Ethoxy ) - Benzoyl ]- Pyrazole -1-yl} -N- Cyclopropyl -4- methyl - Benzamide

3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) -benzoyl] -pyrazol-1-yl}-in anhydrous N, N-dimethylformamide (10 mL)- 4-Methyl-benzoic acid 5 (400 mg, 0.89 mmol), cyclopropylamine (0.89 mmol), EDCI (340 mg, 1.78 mmol), HOBt (272 mg, 1.78 mmol) and diisopropylethylamine (459 mg, 3.56 mmol) was stirred at rt for 18 h. The solvent was evaporated and the residue suspended in EtOAc and washed with water, saturated NaHCO ₃ solution and brine. The organic layer was dried over sodium sulfate. Product 3- {5-amino-4- [3- (2-morpholin-4-yl-ethoxy) -benzoyl] after purification by column chromatography (100/10/1 EtOAc / MeOH / Et ₃ N) -Prazol-1-yl} -N-cyclopropyl-4-methyl-benzamide 6 (45 mg, 10%) was obtained as a pale yellow solid. HPLC (4 min gradient) t _R 1.69 min; MS m / z 490.24 [M + H] ⁺ .

Example  14

3- [5-amino-4- (3- Benzyloxy - Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide  Produce

A. 3- Benzyloxy -Benzoic acid ethyl ester

K ₂ CO ₃ (6.9 g, 50 mmol) and 18-crown-6 are added to a solution of 3-hydroxy-benzoic acid ethyl ester 1 (8.3 g, 50 mmol) in acetone (100 mL) and the mixture is stirred at rt for 18 h. It was. The solid was removed by filtration. The filtrate was concentrated in vacuo to afford 3-benzyloxy-benzoic acid ethyl ester 2 as a colorless liquid.

B. 3- (3- Benzyloxy - Phenyl ) -3-oxo-propionitrile

LDA (1.8 M, 100 mmol, 56 mL) was added to a solution of acetonitrile (4.1 g, 100 mmol) in THF (100 mL, anhydrous) at -78 ° C under nitrogen. The mixture was stirred at -78 ° C for 30 minutes. Then a solution of 3-benzyloxy-benzoic acid ethyl ester 2 in 50 mL of dry THF was added dropwise to the reaction mixture. The mixture was stirred at -78 ° C for 1 hour and then water was added. The organic phase was separated. The pH of the aqueous phase was acidified to about 2 with hydrochloric acid and extracted with EtOAc. The THF and EtOAc layers were combined, washed with water and brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the solid residue was triturated with Et ₂ O and dried in vacuo. The desired product 3- (3-benzyloxy-phenyl) -3-oxo-propionitrile 3 (11.0 g, 87%) was obtained as a light brown solid.

C. 2- (3- Benzyloxy - Benzoyl ) -3-dimethylamino-acrylonitrile

N, N-dimethylformamide dimethyl acetal (10 mL) in 3- (3-benzyloxy-phenyl) -3-oxo-propionitrile 3 (2.5 g, 10 mmol) in DMF (20 mL, anhydrous) Was added and the mixture was stirred at 100 ° C for 3 h. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc as eluent). Product 2- (3-benzyloxy-benzoyl) -3-dimethylamino-acrylonitrile 4 (2.6 g, 90%) was obtained as a pale yellow solid.

D. 3- [5-amino-4- (3- Benzyloxy - Benzoyl ) -Pyrazol-1-yl] -N- Cyclopropyl -4-  methyl - Benzamide

2- (3-benzyloxy-benzoyl) -3-dimethylamino-acrylonitrile 4 (147 mg, 0.5 mmol) and N-cyclopropyl-3-hydrazino-4-methyl-benzamide, trifluoroacetic acid salt 8 (Example 6C, 240 mg, 0.75 mmol) was dissolved in DMF (5 mL) and heated in a microwave oven at 160 ° C. for 30 minutes. Solvent was removed and the residue was purified by column (3: 1 EtOAc / hexanes). Product 3- [5-amino-4- (3-benzyloxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide 6 (120 mg, 52%) as a pale yellow solid Obtained.

Example  15

3- [5-amino-4- (3-hydroxy- Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide  Produce

3- [5-Amino-4- (3-benzyloxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide 6 (200 mg, 0.43 mmol) was dissolved in MeOH (10 mL )). Catalyst 10% palladium (anhydrous) on activated carbon was added and stirred under hydrogen atmosphere for 2 hours. The catalyst was filtered off and the solvent was removed in vacuo. Product 3- [5-amino-4- (3-hydroxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide 7 (140 mg, 87%) as a pale yellow solid Obtained.

Example  16

3- [5-amino-4- (4- methyl - Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide  Produce

A. 2- (4- methyl - Benzoyl ) -3- Phenylamino Acrylonitrile

A mixture of 4-toluoylacetonitrile 1 (4.0 g, 25 mmol) and N, N-diphenylformamidine (4.9 g, 25 mmol) in anhydrous toluene (50 mL) was heated at 85 ° C. for 16 hours under nitrogen. It was. The mixture was cooled to room temperature and 170 mL * 1/4 of hexane was added. The mixture was stirred at room temperature for 5 minutes, forming a yellow precipitate. The solid was collected in a frit flask and washed with hexane to give pure 2- (4-methyl-benzoyl) -3-phenylamino-acrylonitrile 2 (4.5 g, 68%).

B. 3- [5-amino-4- (4- methyl - Benzoyl ) -Pyrazol-1-yl] -N- Cyclopropyl -4- methyl - Benzamide

2- (4-Methyl-benzoyl) -3-phenylamino-acrylonitrile 2 (205 mg, 0.78 mmol) in 8 mL of ethanol, N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoro A mixture of acetic acid salt 7 (Example 6C, 250 mg, 0.78 mmol) and diisopropylethylamine (0.14 mL, 0.78 mmol) was heated at 65 ° C. for 18 hours. The solvent was removed and the residue was purified by silica gel column chromatography (EtOAc / hexanes, gradient 1/3 to 3/1). The product was further purified by trituration with Et ₂ O to give 3- [5-amino-4- (4-methyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide 3 (64 mg, 22%) was obtained as a white solid. HPLC (4-minute gradient) t _R 2.26 min;

Example  17

3- (5-amino-4- Benzoyl - Imidazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide  Produce

A. 3- (5-amino-4- Cyano - Imidazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide

A mixture of 3-amino-N-cyclopropyl-4-methyl-benzamide 1 (380 mg, 2.0 mmol) in 2.0 mL of triethyl orthoformate was heated by microwave at 120 ° C. for 20 minutes. The solvent was removed under reduced pressure. The residue was dissolved in 5 mL of acetic acid followed by addition of aminomalononitrile p -toluenesulfonate (506 mg, 2.0 mmol) and sodium acetate (164 mg, 2.0 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with 20 mL of water and then its pH was adjusted to 8.0 with aqueous NaOH. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers are washed with water (10 mL) and brine (10 mL), dried over MgSO ₄ , filtered, concentrated in vacuo, Evaporated. The residue was purified by silica gel column chromatography (10/1, methylene chloride: methanol) to give 3- (5-amino-4-cyano-imidazol-1-yl) -N-cyclopropyl-4-methyl- Benzamide 3 (170 mg, 30%) was obtained as a colorless solid. HPLC (4-minute gradient) t _R = 1.39 min; MS m / z 282 [M + H].

B. 3- (5-amino-4- Benzoyl - Imidazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide

Phenyl in a solution of 3- (5-amino-4-cyano-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide 3 (56.4 mg, 0.2 mmol) in anhydrous THF (10 ml) Magnesium bromide (1 m, 1 mL) was added at room temperature under nitrogen. After 1 h, HCl solution (3N, 10 ml) was added and the mixture was stirred overnight. The solution was neutralized with dilute aqueous NaOH. The mixture was extracted with ethyl acetate (100 mL × 2), washed with water and dried over Na ₂ SO ₄ . The solvent was evaporated to give a residue, which was purified by HPLC to give 3- (5-amino-4-benzoyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide (56 mg, 78% ) Was obtained as a white solid. LCMS (4 min gradient) t _R = 2.07 min; MS m / z 361.17 [M + H] ⁺

Example  18

3- (5-amino-4- Cyclohexanecarbonyl - Imidazole -1-yl) -N- Cyclopropyl -4- methyl Preparation of Benzamide

Prepared according to a procedure similar to the procedure in Example 17 except that cyclohexyl magnesium bromide was used instead of phenyl magnesium bromide. HPLC (4 min 10-90 gradient) t _R 2.01 min; MS m / z 367.29 [M + H] ⁺ .

Example  19

3- (5-amino-4- Cyclopentanecarbonyl - Imidazole -1-yl) -N- Cyclopropyl -4- methyl Preparation of Benzamide

Prepared according to a procedure similar to that in Example 17 except that cyclopentylmagnesium bromide was used instead of phenyl magnesium bromide. HPLC (4 min 10-90 gradient) t _R 1.92 min; MS m / z 353.22 [M + H] ⁺ .

Example  20

3 -(5-amino-4- Phenylacetyl - Imidazole -1-yl) -N- Cyclopropyl -4- methyl - Benzami Manufacture of de

Prepared according to a procedure similar to the procedure in Example 17 except that benzyl magnesium bromide was used instead of phenyl magnesium bromide. HPLC (4 min 10-90 gradient) t _R 2.14 min; MS m / z 375.20 [M + H] ⁺ .

Example  21

3- [5-amino-4- (3- Isopropylcarbamoyl - Benzoyl ) - Imidazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

A. 3- [5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H- Imidazole -4-carbonyl] -benzoic acid

To a solution of 3-iodobenzoic acid tert-butyl ester (4.6 g) in THF (20 mL) was added cyclohexylmagnesium chloride (2 M in THF, 8.5 mL) at -40 ° C under N ₂ . The solution was kept at -40 ° C to 0 ° C for 20 minutes. 3- (5-Amino-4-cyano-imidazol-1-yl) -N -cyclopropyl-4-methyl-benzamide was added and the reaction was maintained at room temperature for 1 hour. HCl (4 M, 10 mL) was then added and the mixture was heated at 40-45 ° C. overnight. The mixture was neutralized with K ₂ CO ₃ solution, extracted with EtOAc (2 × 100 mL), and the combined organics were dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (EtOAc: MeOH = 6: 1) to afford the desired product (0.46 g).

B. 3- [5-amino-4- (3- Isopropylcarbamoyl - Benzoyl ) - Imidazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide

A solution of acid 4 (160 mg), EDCI (90 mg), and N-hydroxysuccinimide (53 mg) in DMF (2 mL) was reacted overnight at room temperature. Water (12 ml) was added and the solution extracted with EtOAc (15 mL X 2) and dried over Na ₂ S0 ₄ . The solvent was evaporated to give a residue, to which EtOAc (4 mL) and 2-propylamine (1.2 equiv) were added. The reaction was kept at rt for 1 h, then concentrated and the crude product was purified by column chromatography to give the desired product (yield: 80%). HPLC (4 min gradient) t _R = 2.00 min; MS m / z 446.19 [M + H] ⁺ .

Example  22

3- {5-amino-4- [3- (2-dimethylamino- Ethylcarbamoyl ) - Benzoyl ]- Imidazole Preparation of -1-yl} -N-cyclopropyl-4-methyl-benzamide

Prepared according to a procedure analogous to that in Example 21 except that 2-dimethylaminoethylamine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 2.18 min; MS m / z 475.15 [M + H] ⁺ .

Example  23

3- [5-amino-4- (3- Ethylcarbamoyl - Benzoyl ) - Imidazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

Prepared according to a procedure similar to the procedure in Example 21 except that ethylamine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.70 min; MS m / z 432.18 [M + H] ⁺ .

Example  24

3- [5-amino-4- (3- Methylcarbamoyl - Benzoyl ) - Imidazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

Prepared according to a procedure similar to that in Example 21, except that methylamine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.61 min; MS m / z 418.15 [M + H] ⁺ .

Example  25

3- [5-amino-4- (3- Cyclopropylcarbamoyl - Benzoyl ) - Imidazole -1-yl] -N- Cyclo Preparation of Propyl-4-methyl-Benzamide

Prepared according to a procedure analogous to that in Example 21 except that cyclopropylamine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.74 min; MS m / z 444.14 [M + H] ⁺ .

Example  26

3- [5-amino-4- (3- Cyclopentylcarbamoyl - Benzoyl ) - Imidazole -1-yl] -N- Cycloph Preparation of Lofil-4-methyl-benzamide

Prepared according to a procedure analogous to that in Example 21 except that cyclopentylamine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.95 min; MS m / z 472.24 [M + H] ⁺ .

Example  27

3 -{5-amino-4- [3- (morpholine-4-carbonyl)- Benzoyl ]- Imidazole -1-yl} -N- Cyclo Preparation of Propyl-4-methyl-Benzamide

Prepared according to a procedure similar to that in Example 21 except that morpholine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.67 min; MS m / z 474.17 [M + H] ⁺ .

Example  28

3- {5-amino-4- [3- (cyclopropylmethyl-carbamoyl) -benzoyl] - imidazolidin-1-yl} - Preparation of benzamide -N- cyclopropyl-4-methyl

Prepared according to a procedure similar to the procedure in Example 21 except that cyclopropylmethylamine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.86 min; MS m / z 458.23 [M + H] ⁺ .

Example  29

3- [5-amino-4- ( Tetrahydro -Pyran-4-carbonyl)- Imidazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

A. 4- Bromo - Tetrahydro Piran

Tetrahydro-4 H -pyran-4-ol (1.0 g, 10 mmol), carbon tetrabromide (3.6 g, 11 mmol) and triphenylphosphine (3.1 g, 12 mmol) were CH ₂ Cl ₂ (25 mL) and stirred overnight at room temperature. The crude reaction mixture was concentrated and then purified by flash chromatography on silica gel (EtOAc: hexane = 1: 20) to give the product (1.4 g, 87%) as colorless oil.

B. 3- [5-amino-4- ( Tetrahydro -Pyran-4-carbonyl)- Imidazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide

A solution of 4-bromo-tetrahydro-pyran (0.82 g, 5 mmol) in dry THF (10 mL) was added to a suspension of magnesium (132 mg, 5.5 mmol) and iodine (25 mg) in dry THF (20 mL). It was added dropwise at 50 ° C. under N ₂ . After addition the mixture was stirred at 50 ° C. for 30 minutes and then cooled to room temperature. Then a THF (10 mL) solution of 3- (5-amino-4-cyano-imidazol-1-yl) -N -cyclopropyl-4-methyl-benzamide (90 mg, 0.32 mmol) was added to the reaction mixture. Was added and stirred at room temperature for 3 hours, then quenched with HCl (2N) and stirred overnight at room temperature. The pH of the solution was adjusted to about pH 8 with saturated aqueous K ₂ CO ₃ and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na ₂ S0 ₄ and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc to EtOAc: MeOH: Et ₃ N = 100: 10: 1) to give the product (35 mg, 30%) as a beige solid. HPLC (4 min gradient) t _R = 3.05 min; MS m / z 369.18 [M + H] ⁺ .

Example  30

3- (5-amino-4- Benzoyl -3- Methoxy - Pyrazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide  Produce

A. 2- Benzoyl -3,3- Vis - Methylsulfa Nyl-acrylonitrile

To a stirred solution of benzoylacetonitrile 1 (7.50 g, 51.7 mmol) in THF (100 ml) was added anhydrous sodium hydride (2.61 g, 103 mmol) at 0 ° C. The resulting suspension was stirred at 0 ° C. for 45 minutes and then carbon disulfide (2.39 ml, 54.8 mmol) was added. The reaction was then stirred at rt for 2 h. The resulting red solution was cooled to 0 ° C and iodomethane (6.75 ml, 109 mmol) was added. The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo. The residue was diluted with ether and washed with brine. The aqueous layer was extracted twice with ether. The combined organic layers were washed twice with 5% sodium thiosulfate and then brine. The organic layer was dried over MgSO ₄ , filtered and concentrated to give 2-benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (9.5 g, 74%) as a yellow powder. The product was used in the next step without further purification.

B. 3- (5-amino-4- Benzoyl -3- Methoxy - Pyrazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide

Sodium (317 mg, 13.8 mmol) was added to methanol (10 ml) at 0 ° C. After consuming all the sodium, the solution of sodium methoxide was stirred with 2-benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (3.12 g, 12.5 mmol) in dioxane (30 ml) at 0 ° C. To the prepared solution. The reaction was warmed to room temperature and then heated to 80 ° C. for 3 hours. The dark red solution is cooled to room temperature and the N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (4.00 g, 12.5 mmol) and diisopropylethylamine in dioxane (15 ml) (2.18 ml, 12.5 mmol) was added to the solution. The mixture was heated to 85 ° C for an additional 6 hours. The solvent was removed in vacuo. The residue was diluted with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , gradient 75 to 90% EtOAc / hexanes) and recrystallized from EtOAc to afford the desired 3- (5-amino-4-benzoyl-3-methoxy-pyrazole- 1-yl) -N-cyclopropyl-4-methyl-benzamide 3 (950 mg, 19%) was obtained as a white solid. HPLC (4 min 10-90 gradient) t _R 2.33 min;

Example  31

3 -(5-amino-4- Benzoyl -3- Ethoxy - Pyrazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide of Produce

Ethanol (0.47 ml, 8.0 mmol) was added to a suspension of anhydrous sodium hydride (41 mg, 1.6 mmol) in dioxane (2 ml). The mixture was stirred at rt for 10 min. 2-benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.20 g, 0.80 mmol) was added and the mixture was stirred at 85 ° C. for 2.5 h. The mixture was cooled to room temperature. N -cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.26 g, 0.80 mmol) was added and the reaction was heated to 85 ° C. for an additional 3 hours. The solvent was removed in vacuo. The residue was diluted with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , gradient 75% to 85% EtOAc / hexanes). The product was further purified by washing with a warm mixture of EtOAc and hexanes to afford the desired 3- (5-amino-4-benzoyl-3-ethoxy-pyrazol-1-yl) -N-cyclopropyl-4-methyl- Benzamide 4 (27 mg, 8.3%) was obtained as a white solid. HPLC (4 min 10-90 gradient) t _R 2.37 min;

Example  32

Preparation of 3- [5-amino-4- benzoyl- 3- (2 -methoxy - ethoxy ) -pyrazol-1-yl] -N- cyclopropyl -4- methyl - benzamide

Anhydrous sodium hydride (21 mg, 0.84 mmol) at 0 ° C. was added to a solution of 2-methoxyethanol (0.63 ml, 8.0 mmol) in dioxane (2 ml). The mixture was stirred at rt for 30 min. 2-benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.20 g, 0.80 mmol) was added and the mixture was stirred at 85 ° C for 4 h. The mixture was cooled to room temperature. N -cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.26 g, 0.80 mmol) was added followed by diisopropylethylamine (0.14 ml, 0.80 mmol) and the reaction was brought to 85 ° C. Heated for an additional 11 h. The solvent was removed in vacuo. The residue was diluted with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , gradient 70% to 90% EtOAc / hexanes). The product was further purified by washing with a warm mixture of EtOAc and hexanes to afford the desired 3- [5-amino-4-benzoyl-3- (2-methoxy-ethoxy) -pyrazol-1-yl] -N- Cyclopropyl-4-methyl-benzamide 5 (60 mg, 17%) was obtained as a white solid. HPLC (4 min 10-90 gradient) t _R 2.17 min;

Example  33

3 -[5-amino-4- Benzoyl -3- (2- Benzyloxy - Ethoxy ) - Pyrazole -1-yl] -N- Cyclopropyl - 4- methyl - Benzamide of Produce

Anhydrous sodium hydride (21 mg, 0.84 mmol) was added to a solution of 2-benzyloxyethanol (1.1 ml, 8.0 mmol) in dioxane (2 ml) at 0 ° C. The mixture was stirred at rt for 35 min. 2-benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.20 g, 0.80 mmol) was added and the mixture was stirred at 80 ° C. for 2.5 h. The mixture was cooled to room temperature. N -cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.26 g, 0.80 mmol) was added and the reaction was heated to 80 ° C. for an additional 8.5 h. After cooling the reaction mixture to room temperature, the solvent was removed in vacuo. The residue was diluted with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , gradient 60% to 85% EtOAc / hexanes). The product was further purified by washing with warm EtOAc to afford the desired 3- [5-amino-4-benzoyl-3- (2-benzyloxy-ethoxy) -pyrazol-1-yl] -N-cyclopropyl- 4-Methyl-benzamide 6 (74 mg, 18%) was obtained as an off-white solid. HPLC (4 min 10-90 gradient) t _R 2.57 min;

Example  34

4- [5-amino-4- Benzoyl -1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H- Pyrazole -3-yloxy] -piperidine-1-carboxylic acid tert Preparation of -Butyl Ester

Anhydrous sodium hydride (41.0 mg, 1.60 mmol) was added to a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 7 (0.565 g, 2.81 mmol) in dioxane (2 ml) at 0 ° C. Added. The mixture was stirred at rt for 45 min. 2-benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.20 g, 0.80 mmol) was added and the mixture was stirred at 65 ° C for 4 h. The mixture was cooled to room temperature. N -cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.26 g, 0.80 mmol) was added and the reaction was heated to 80 ° C. for an additional 3 hours. After cooling the reaction mixture to room temperature, the solvent was removed in vacuo. The residue was diluted with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , gradient 65% to 85% EtOAc / hexanes). The product was further purified by washing with warm EtOAc to afford the desired 4- [5-amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazol-3-yljade. C] -piperidine-1-carboxylic acid tert-butyl ester 8 (70 mg, 16%) was obtained as off-white solid. HPLC (4 min 10-90 gradient) t _R 2.63 min;

Example  35

3- [5-amino-4- Benzoyl -3- (piperidine-4- Iloxy ) -Pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide, Trifluoroacetate  Preparation of Salt

4- [5-amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazol-3-yloxy] -piperidine in dichloromethane (2.0 ml) -1-carboxylic acid tert-butyl ester 8 (5.0 mg, 0.0089 mmol) was added trifluoroacetic acid (0.5 ml). The mixture was stirred at room temperature for 3 hours. Volatiles under vacuum Remove and the residue is washed with ether and a small amount of EtOAc to afford the desired 3- [5-amino-4-benzoyl-3- (piperidin-4-yloxy) -pyrazol-1-yl] -N-cyclo Propyl-4-methyl-benzamide, trifluoroacetate salt 9 (3.0 mg, 59%) was obtained as a white solid. HPLC (4 min 10-90 gradient) t _R 1.75 min;

Example  36

3 -(5-amino-4- Benzoyl -3- Methylsulfanyl - Pyrazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide of Produce

To a solution of benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.218 g, 0.874 mmol) in ethanol (5 ml) N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluor Roacetic acid salt (0.243 g, 0.874 mmol) and diisopropylethylamine (0.152 ml, 0.874 mmol) were added. The mixture was heated to 65 ° C for 18 h. The mixture was cooled to room temperature. The solvent was removed in vacuo. The residue was diluted with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (SiO ₂ , gradient 65% to 100% EtOAc / hexanes). The product was further purified by washing with a warm mixture of EtOAc and hexanes to afford the desired 3- (5-amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl -Benzamide 10 (57 mg, 16%) was obtained as off-white solid. HPLC (4 min 10-90 gradient) t _R 2.34 min;

Example  37

3- (5-amino-4- Benzoyl -3- Methanesulfonyl - Pyrazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide  Produce

3- (5-Amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide 10 (40 mg, 0.098 mmol) in dichloromethane (1 ml) To the suspension of) was added 3-chloroperoxybenzoic acid (70-75%, 53 mg, 0.22 mmol). The resulting solution was stirred at room temperature for 2 hours, then at 4 ° C. overnight Stored. Upon warming to room temperature the product began to precipitate. The white solid was collected on a frit funnel and washed with dichloromethane and ether to afford the desired 3- (5-amino-4-benzoyl-3-methanesulfonyl-pyrazol-1-yl) -N-cyclopropyl- 4-methyl-benzamide 11 (27 mg, 63%) was obtained. HPLC (4 min 10-90 gradient) t _R 1.98 min;

Example  38

5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -3- Methylsulfa Preparation of Neyl-1H-pyrazole-4-carboxylic acid amide

N-cyclopropyl-3-hydrazino-4-methyl-benzamide in a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylamide 12 (100 mg, 0.574 mmol) in ethanol (5 ml) Trifluoroacetic acid salt (0.183 g, 0.574 mmol) and diisopropylethylamine (0.100 ml, 0.574 mmol) were added. The mixture was heated to 65 ° C for 18 h. The mixture was cooled to room temperature. The solvent was removed in vacuo. EtOAc was added to the residue to precipitate a solid. The solid was collected on a frit funnel and washed with EtOAc to afford the desired 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methylsulfanyl-1H-pyrazole-4 -Carboxylic acid amide 13 was obtained. HPLC (4 min 10-90 gradient) t _R 1.98 min;

Example  39

5 -Amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -3- Methanesulfonyl Preparation of -1H-pyrazole-4-carboxylic acid amide

5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide 13 (100 mg) in dichloromethane (3 ml) To the suspension of, 0.289 mmol), 3-chloroperoxybenzoic acid (70-75%, 157 mg, 0.637 mmol) was added. The resulting clear solution was stirred at rt for 16 h. Saturated NaHCO ₃ solution was added and the mixture was vigorously stirred for 1 minute. The resulting suspension is filtered on a frit funnel and the collected solid is washed three times with ether three times with H ₂ O to give the desired 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl). 3-Methanesulfonyl-1H-pyrazole-4-carboxylic acid amide 14 (87 mg, 80%) was obtained as a white solid. HPLC (4 min 10-90 gradient) t _R 1.66 min;

Example  40

5 -Amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -3- Methylsulfanyl Preparation of -1H-pyrazole-4-carboxylic acid ethyl ester

N-cyclopropyl-3-hydrazino-4-methyl-benz in a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester 15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) Amide trifluoroacetic acid salt (0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol) were added. The mixture was heated to 65 ° C for 2 h. The mixture was cooled to room temperature. The solvent was removed in vacuo. EtOAc and ether were added to the residue and a solid precipitated out. The solid was collected on a frit funnel and washed with EtOAc to afford the desired 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methylsulfanyl-1H-pyrazole-4 -Carboxylic acid ethyl ester 16 (80 mg, 59%) was obtained as a white solid.

Example  41

3 -[5-amino-4- (3- Chlorobenzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- methyl - Benzamide of Produce

A. 2- (3- Chlorobenzoyl ) -3- Phenylaminoacrylonitrile

A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 equiv) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 equiv) in 25 mL of toluene was stirred at room temperature for 2 hours and then at 100 ° C. Heated overnight. The solution was cooled down and diluted with hexanes. The resulting solid was filtered and dried to give the desired product (566 mg, 75%). HPLC (4 min 10-95 gradient) t _R 2.97 min;

B. 3- [5-amino-4- (3- Chlorobenzoyl ) -Pyrazol-1-yl]- N - Cyclopropyl -4- methyl - Benzamide

2- (3-chlorobenzoyl) -3-phenylaminoacrylonitrile (63 mg, 0.22 mmol, 1.0 equiv) in 10 mL of ethanol, N -cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (72 mg, 0.22 mmol, 1 equiv) and a solution of triethylamine (31 μL, 0.22 mmol, 1.0 equiv) were heated to 65 ° C. for 20 h. After cooling, the mixture was concentrated and the residue was purified by flash chromatography, eluting with 7/3 hexanes / ethyl acetate to remove byproducts on packed silica gel, and then with 3/2 ethyl acetate / hexanes. Compound (33 mg, 38%) was obtained as a brown solid. HPLC (4 min 10-95 gradient) t _R 2.35 min;

Example  42

3- [5-amino-4- (3- methyl - Benzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- Of methylbenzamide  Produce

Prepared according to a procedure similar to that of Example 41, except that 3-methylbenzoylacetonitrile was used instead of 3-chlorobenzoylacetonitrile. HPLC (4 min 10-95 gradient) t _R 2.27 min;

Example  43

3- [5-amino-4- (2- Methylbenzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- methyl - Benzamide  Produce

Prepared according to a procedure similar to that of Example 41, except that 2-methylbenzoylacetonitrile was used instead of 3-chlorobenzoylacetonitrile. HPLC (4 min 10-90 gradient) t _R 2.21 min; MS m / z 375.15 [M + H] ⁺ .

Example  44

3- [5-amino-4- (2- Methoxy - Benzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide  Produce

Prepared according to a procedure analogous to that of Example 41 except that 2-methoxybenzoylacetonitrile was used instead of 3-chlorobenzoylacetonitrile. HPLC (4 min 10-90 gradient) t _R 2.03 min; MS m / z 391.16 [M + H] ⁺ .

Example  45

3- [5-amino-4- (4- Chlorobenzoyl ) - Pyrazole -1-yl] -N- Cyclopropyl -4- methyl - Benzamide  Produce

Prepared according to a procedure similar to that of Example 41, except that 3-methylbenzoylacetonitrile was used instead of 3-chlorobenzoylacetonitrile. HPLC (4 min 10-90 gradient) t _R 1.65 min; MS m / z 394.2 [M + H] ⁺ .

Example  46

3- [5-amino-4- (2- Chlorobenzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- methyl - Benzamide  Produce

A. 2- (2- Chlorobenzoyl ) -3- Phenylaminoacrylonitrile

A solution of 2-chlorobenzoylacetonitrile (1.0 g, 5.6 mmol, 1.0 equiv) and diphenylformamidine (1.10 g, 5.6 mmol, 1.0 equiv) in 50 mL of toluene was heated to 85 ° C. overnight. Removal of the heat source caused the desired product to slowly precipitate out of solution. The resulting solid was filtered and dried to give the desired product (826 mg, 52%). HPLC (4 min 10-90 gradient) t _R 3.13 min; MS m / z 283.2 [M + H] ⁺ .

B. 3- [5-amino-4- (2- Chlorobenzoyl ) -Pyrazol-1-yl]- N - Cyclopropyl -4- methyl - Benzamide

2- (2-chlorobenzoyl) -3-phenylaminoacrylonitrile (93 mg, 0.33 mmol, 1.0 equiv) in 20 mL of ethanol, N -cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (104 mg, 0.33 mmol, 1 equiv) and a solution of triethylamine (31 μL, 0.22 mmol, 1.0 equiv) were heated to 60 ° C. for 48 h. After cooling, the mixture was concentrated and the residue dissolved in a minimum amount of ethyl acetate. 100 ml of diethyl ether were added and the precipitate was filtered and dried to give the desired product (50 mg, 39%). HPLC (4 min 10-90 gradient) t _R 2.51 min;

Example  47

3- [5-amino-4- (3- Methoxy - Benzoyl ) - Pyrazole -1-yl] -4, N-dimethyl- Benzamide  Produce

A. 3- Methoxybenzoylacetonitrile

To a stirred solution of ethyl 3-methoxybenzoate (3.05 mL, 18.6 mmol, 1. equiv) and acetonitrile (1.19 mL, 22.9 mmol, 1.23 equiv) in 5 mL THF, via cannula at -50 ° C. under N _2. Freshly prepared solution of LDA (diisopropylamine, 5.3 mL, 38.0 mmol, 2.04 equiv and 2.5 M n-butyllithium in hexane, 15.25 mL, 38.0 mmol, 2.04 equiv) was added. The reaction was stirred at this temperature for 3 hours and then warmed to 0 ° C. for 1 hour. The reaction was quenched with 10 mL saturated NH ₄ Cl and warmed to room temperature. The mixture was extracted with EtOAc and the organic layer was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel to give the product as off white solid.

B. 2- (3- Methoxybenzoyl ) -3- Phenylamino - Acrylonitrile

A solution of 3-methoxybenzoylacetonitrile (1.20 g, 68.5 mmol, 1.0 equiv) and diphenylformamidine (1.34 g, 68.5 mmol, 1.0 equiv) in 25 mL of toluene was stirred at room temperature for 2 hours and then 100 Heated to C overnight. The solution was cooled down and diluted with hexanes. The resulting solid was filtered and dried to give the desired product. HPLC (4 min 10-90 gradient) t _R 3.05 min; MS m / z 279.2 [M + H] ⁺ .

C. 3- [5-amino-4- (3- Methoxybenzoyl ) - Pyrazole -1-yl] -4- methyl -Benzoic acid

2- (3-chlorobenzoyl) -3-phenylaminoacrylonitrile (63 mg, 0.22 mmol, 1.0 equiv) in 10 mL of ethanol, 3-hydrazino-4-methylbenzoic acid hydrochloride (72 mg, 0.22 mmol, 1 Equivalent) and triethylamine (31 μL, 0.22 mmol, 1.0 equiv) were heated to 65 ° C. for 20 h. After cooling, the mixture was concentrated and the residue was purified by flash chromatography, eluting with 7/3 hexanes / ethyl acetate to remove byproducts on packed silica gel, and then with 3/2 ethyl acetate / hexanes. Compound (15 mg, 32%) was obtained as a brown solid. HPLC (4 min 10-90 gradient) t _R 2.13. Min; MS m / z 352.2 [M + H] ⁺ .

D. 3- [5-amino-4- (3- Methoxybenzoyl ) - Pyrazole -1-yl] -4, N-dimethyl- Benzamide

EDCI in a stirred solution of 3- [5-amino-4- (3-methoxybenzoyl) -pyrazol-1-yl] -4-methylbenzoic acid C (50 mg, 0.14 mmol, 1.0 equiv) in 10 mL DMF (41 mg 0.21 mmol, 1.5 equiv), HOBt (29 mg, 1.5 mmol, 2.0 equiv) and diisopropylethylamine (55 mg, 0.43 mmol, 3.0 equiv) were added and the solution was stirred at room temperature for 15 minutes , Methylamine hydrochloride (13 mg, 0.19 mmol, 1.5 equiv) was added and the reaction stirred for 1 h. The mixture was diluted with EtOAc (300 mL), washed with water (2 × 25 mL) and brine (25 mL), dried (Na ₂ SO ₄ ) and concentrated. The product was purified by flash chromatography on silica gel to give the product (15 mg, 32%) as a brown solid: HPLC (4 min 10-90 gradient) t _R 1.97 min; MS m / z 365.2 [M + H] ⁺ .

Example  48

5 -Amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H- Pyrazole -4- Carboxyl Preparation of Acid Ethyl Ester

A. 5-amino-1- (5- Carboxy -2- methyl - Phenyl ) -1H- Pyrazole -4- Carboxylic acid  Ethyl ester

Ethyl (ethoxymethylene) cyanoacrylate (399 mg, 2.36 mmol) in a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 478 mg, 2.36 mmol, 1.0 equiv) in 20 mL of ethanol , 1.0 equiv) and triethylamine (329 μL, 2.36 mmol, 1.0 equiv) were added and the mixture was heated at 65 ° C. for 5 h. After standing at room temperature overnight, additional 3-hydrazino-4-methylbenzoic acid hydrochloride (159 mg, 0.78 mmol, 0.3 equiv) and triethylamine (110 μL, 0.78 mmol, 0.3 equiv) were added and 2.5 h Heated during. The mixture was cooled to rt and concentrated. The crude residue was purified by flash chromatography on silica gel (gradient elution: 1/1 in 7/3 hexanes / EtOAc to elute byproducts, and then from EtOAc to 9/1 EtOAc / MeOH to elute product) (464 mg, 68%) was obtained as a brown solid. HPLC (4 min 10-95 gradient) t _R 1.87 min;

B. 5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H-pyrazole-4- Carboxylic acid  Ethyl ester

5-amino-1- (5-carboxy-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester (47 mg, 0.16 mmol, in DMF (5 mL) stirred at room temperature for 15 minutes. 1.0 equivalent), EDCI (62 mg, 0.32 mmol, 2.0 equiv), HOBt (44 mg, 0.32 mmol, 2.0 equiv) and cyclopropylamine (119 μL, 0.32 mmol, 2.0 equiv) in a solution of 23 μL, 0.32 mmol, 2.0 equiv) was added. After stirring overnight, the solution was diluted with EtOAc and water, and the organic layer was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The crude residue was purified by flash chromatography on silica gel eluting with 8/2 EtOAc / hexanes to give the product (42 mg, 79%) as a colorless oil. HPLC (4 min 10-95 gradient) t _R 1.84 min;

Example  49

Preparation of 5 -Amino-1- (5- cyclopropylcarbamoyl- 2- methyl - phenyl ) -3- methyl- 1H- pyrazole -4-carboxylic acid ethyl ester

A. 5-amino-1- (5- Carboxy -2- methyl - Phenyl ) -3- methyl -1H-pyrazole-4- Carboxylic acid  Ethyl s Ter

Ethyl 2-cyano-3-ethoxy-but-2-enoic acid in a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 353 mg, 1.74 mmol, 1.0 equiv) in 15 mL of ethanol Ester (prepared as described in Xia et al., J. Med . Chem . , 1997, 40 , 4372) (319 mg, 1.746 mmol, 1.0 equiv) and triethylamine (242 μL, 1.74 mmol, 1.0 equiv) was added and the mixture was heated at 65 ° C overnight. The mixture was cooled to rt and concentrated. The crude residue was loaded with flash chromatography on silica gel (CH ₂ Cl ₂ , packed and gradient eluted with 6/4 hexanes / EtOAc to elute byproducts, then 8/2 EtOAc / to elute product Eluting with 8/2 EtOAc / MeOH in hexane) to afford the product (464 mg, 68%) as a brown solid. HPLC (4 min 10-95 gradient) t _R 1.97 min; MS m / z 304.1 [M + H] ⁺ .

B. 5-Amino-1- (5- cyclopropylcarbamoyl- 2- methyl - phenyl ) -3- methyl- 1H-pyrazole -4 -carboxylic acid ethyl ester

5-amino-1- (5-carboxy-2-methyl-phenyl) -3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (150 mg in DMF (5 mL) stirred at room temperature for 15 minutes , 0.49 mmol, 1.0 equiv), EDCI (190 mg, 0.98 mmol, 2.0 equiv), HOBt (134 mg, 0.98 mmol, 2.0 equiv) and diisopropylethyl amine (362 μL, 0.98 mmol, 2.0 equiv) in a solution Cyclopropylamine (68 μL, 0.98 mmol, 2.0 equiv) was added. After stirring overnight, the solution was diluted with EtOAc and water, and the organic layer was washed with water (2 ×) and brine, dried (Na ₂ SO ₄ ) and concentrated. The crude residue was purified by flash chromatography on silica gel (gradient elution, 3/2 EtOAc / hexanes then 100% EtOAc) to give the product (29 mg, 17%) as a white solid. HPLC (4 min 10-95 gradient) t _R 1.97 min;

Example  50

5-amino-3-[(3- Chloro - Benzylcarbamoyl ) - Methoxy ] -1- (5- Cyclopropylcarbamoyl Preparation of 2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester

A. 5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -3- (2-hydroxy- Ethoxy ) -1H-pyrazole-4-carboxylic acid ethyl ester

Cyano- [1,3] dioxolane-2-ylidene-acetic acid ethyl ester in 20 mL of ethanol (prepared as described in Neidlein and Kikelj, Synthesis , 1988 , 981), 266 mg, 1.45 mmol, 1.0 Equivalents), N -cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetate (Example 6C, 463 mg, 1.45 mmol, 1.0 equiv) and triethylamine (405 μL, 2.9 mmol, 2.0 equiv The stirred solution of) was heated to 65 ° C overnight. After cooling to room temperature, the mixture was concentrated and the residue was purified by flash chromatography on silica gel (eluted with 1/1 hexanes / EtOAc and then 100% EtOAc) to afford the desired compound (350 mg, 62%) as a tan solid. Obtained as. HPLC (4 min 10-95 gradient) t _R 1.59 min;

B. 5-amino-3- Carboxymethoxy -1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H-pyrazole-4-carboxylic acid ethyl ester

To a stirred solution of alcohol 50A (48 mg, 0.12 mmol, 1.0 equiv) in 5 mL of acetonitrile was added 2,2 ', 6,6'-tetramethylpiperidinyloxyl (TEMPO) (catalytic), The solution was heated to 35 ° C. Then a solution of sodium chlorite (17 mg, 0.24 mmol, 2.0 equiv) in 2 mL of water (2 mL) and an aqueous solution of sodium hypochlorite diluted with 2% (1 mL) were added dropwise at the same time, and heating was performed for 24 hours. Lasted. A bright orange color appeared. The reaction was cooled to rt, diluted with water and then quenched with 1 M Na ₂ SO ₃ and stirred for 30 minutes. The mixture was washed with EtOAc, then the pH of the aqueous layer was adjusted to pH = 8 to pH = 2 with 3 M HCl and extracted with CH ₂ Cl ₂ . The CH ₂ Cl ₂ extract was dried and concentrated to give the product as a yellow solid. HPLC (4 min 10-95 gradient) t _R 1.70 min;

C. 5-amino-3-[(3- Chloro Benzylcarbamoyl) Methoxy ] -1- (5- Cyclopropyl Carbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester

3-chloro at room temperature in a stirred solution of acid 50B (28 mg, 0.7 mmol, 1.0 equiv), EDCI (32 mg, 0.17 mmol, 2.4 equiv), HOBt (22 mg, 0.16 mmol, 2.4 mmol) in 3.0 mL DMF Benzylamine (18 μL, 0.07 mmol, 1.0 equiv) was added and the mixture was stirred overnight. The mixture was diluted with EtOAc, washed with water (× 2) and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 9/1 EtOAc / hexanes to give the product (16 mg, 44%) as a clear oil. HPLC (4 min 10-95 gradient) t _R 2.34 min;

Example  51

3- (5-amino-4- Benzoyl - Pyrazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide  My article

A. 3-hydrazino-4- Methylbenzoic acid Hydrochloride

Ice water was used to cool a solution of 3-amino-4-methyl benzoic acid 1 (100 g, 0.66 mol, 1.0 equiv) in water (1.78 L) to 0-5 ° C. Concentrated HCl (1.78 L) and sodium nitrite (68.5 g, 0.99 mol, 1.5 equiv) were added sequentially at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C. for 1 hour. Stannous chloride dihydrate (336 g, 1.488 mol, 2.25 equiv) in concentrated HCl (540 ml) was added at 0-5 ° C. The mixture was stirred at the same temperature for 2 hours. The solid formed in the course of the reaction was filtered and washed with water (3 × 500 ml). The crude material (110 g) obtained by drying at 25-30 [deg.] C. under vacuum for 15 hours was then dissolved in ethanol (1 L) and stirred at 70 [deg.] C. for 1 hour. The material was filtered at high temperature, washed with ethanol (50 ml) and air dried to give pure hydrazine 2 (60 g, 45%) as off-white solid.

B. 3- (5-amino-4- Benzoyl - Pyrazole -1-yl) -4- Methylbenzoic acid

To a stirred solution of hydrazine 2 (59 g, 0.29 mol, 1.0 eq.) In ethanol (4.5 L) was added 3 (65 g, 0.262 mol, 0.9 eq., Preparation method: Grothasu, Davis, J. Am. Chem . , 58 , 1334 (1936)] and triethylamine (29 g, 0.29 mol, 1.0 equiv). The mixture was heated to 65 ° C. The reaction mixture was homogeneous at 65 ° C. and stirred at 65 ° C. for 4 hours. The product precipitated during the reaction. The solid was filtered under high temperature conditions and dried to give acid 4 (45 g, 53%) as off-white crystalline solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm x 250 mm, 1.0 mL / min, mobile phase: 0.1% TEA in H ₂ O / acetonitrile 40/60 eluting for 30 min) t _R 2.12 min , 96.6% purity; _{^{1 H NMR (DMSO- d 6,}} 400 MHz) was consistent with Example 3.

C. 3- (5-amino-4- Benzoyl - Pyrazole -1-yl) -N- Cyclopropyl -4- Methylbenzamide

To a stirred solution of acid 4 (46 g, 0.143 mol, 1.0 equiv) in DMF (1.9 L), EDCI (57.5 g, 0.299 mol, 2.09 equiv), HOBt (41.4 g, 0.306, 2.14 equiv) and diisopropylethyl Amine (76.6 g, 0.59 mol, 4.15 equiv) was added and the solution stirred for 20 minutes at room temperature. It was then cooled to 15-20 ° C., cyclopropylamine (20.6 g, 0.36 mol, 2.51 equiv) was added and stirred at room temperature. The reaction was monitored by TLC. After 14 hours, the reaction was not complete so additional cyclopropylamine (9.36 g, 0.16 mol, 1.14 equiv) was added and stirring was continued for 2 hours. DMF was removed at 50-55 ° C. under reduced pressure. To the residue was added EtOAc (1 L) and water (500 ml) and the mixture was stirred for 10 minutes. The mixture was extracted and the organic layer collected. The aqueous layer was extracted with EtOAc (2 x 250 ml). The combined organic layers were washed with sodium bicarbonate (2 x 500 ml) and brine (2 x 500 ml), dried over anhydrous sodium sulfate and concentrated. To the residue was added EtOAc / dichloromethane / hexane (50 ml / 50 ml / 50 ml), the mixture was stirred for 10 minutes and filtered to give the product (34.1 g, 65.7%) as an off-white crystalline solid. HPLC (Waters Ex-Tera 5 Micron C18 Column 4.6 mm × 250 mm, 1.0 mL / min, Mobile Phase: 0.1% TEA in H ₂ O / acetonitrile 50/50, 30 min. Eluted) t _R 5.53 min, 99.3% purity; MS m / z 360 [M] ⁺ ; _{^{1 H NMR (DMSO- d 6,}} 400 MHz) was consistent with Example 4. Fig.

Example  52

3- [5-amino-4- (3- Cyanobenzoyl ) - Pyrazole -1 day] -N - Cyclopropyl -4- Methylbenzamide  Produce

Solution of 3- [5-amino-4- (3-iodobenzoyl) -pyrazol-1-yl] -N -cyclopropyl-4-methylbenzamide (110 mg, 0.23 mmol) in DMF (5 mL) To CuCN (40 mg, 0.45 mmol) and tetrakis (triphenylphosphine) palladium (catalyst) were added and the mixture was heated at 100 ° C. under N ₂ overnight. The solvent was removed, the residue was suspended in EtOAc and the solids were filtered off. The filtrate was washed with water and brine, dried over Na ₂ S0 ₄ and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc). Product (30 mg, 34%) was obtained as a beige solid. HPLC (4 min 10-90 gradient) t _R 2.02 min; MS m / z 386.13 [M + H] ⁺ .

Example  53

3- [5-amino-4- (3- [1,3,4] Oxadiazole -2 days- Benzoyl ) - Pyrazole -1 day]- N - Cyclopropyl Preparation of 4-methylbenzamide

A. 3- [5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H-pyrazole-4-carbonyl] -benzoic acid

Stirred of 3- [5-amino-4- (3-formylbenzoyl) -pyrazol-1-yl] -N -cyclopropyl-4-methylbenzamide (900 mg) in CH ₃ CN (25 mL) To the solution was added NaH ₂ PO ₄ (55 mg in 2 mL water) and H ₂ O ₂ (1.3 g, 30% solution in water), then an aqueous solution of NaClO ₂ (365 mg) was added dropwise at 10 ° C. The mixture was stirred at this temperature for 4 hours and then Na ₂ SO ₃ was added. The solvent was removed and the residue was dissolved in EtOAc and the organic layer was washed with water and brine and concentrated. The crude product was purified by column chromatography on silica gel (eluting with EtOAc followed by EtOAC: AcOH = 100: 1) to afford the desired intermediate (345 mg, 37%) as a beige foam.

B. 3- [5-amino-4- (3- Hydrazinocarbonylbenzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- Methylbenzamide

Compound 53A (50 mg, 0.12 mmol), t -butyl carbazate (33 mg, 0.24 mmol), EDCI (46 mg, 0.24 mmol) and HOBt (37 Mg, 0.24 mmol) were added to DMF (5 mL, anhydrous) Dissolved in and stirred overnight at room temperature. The solvent is removed, the residue is dissolved in EtOAc and the organics are water, K ₂ CO ₃ Washed with aqueous solution and brine and dried over Na ₂ SO ₄ . Then TFA / DCE (5 mL, 1: 1) was added and stirred at room temperature for 30 minutes. The solvent was removed and the residue was dissolved in EtOAc, washed with aqueous K ₂ CO ₃ solution and dried over Na ₂ SO ₄ . Removal of solvent gave compound B (45 mg, 88%) as a beige solid.

C. 3- [5-amino-4- (3- [1,3,4] Oxadiazole -2 days- Benzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- Methylbenzamide

Trimethyl orthoformate (2 mL) was added to compound 53B in MeOH (2 mL) and stirred at rt overnight. The solvent was removed, the solid residue was dissolved in 1,4-dioxane, 5 drops of a 4 M solution of HCl in dioxane was added and heated at 120 ° C. for 30 minutes using microwave. The solvent is removed, the residue is dissolved in EtOAc, the organics are washed with water and brine and the crude product is purified by preparative TLC (EtOAc: MeOH = 95: 5) to give the product as a beige solid (25 mg, 63 %) Was obtained. HPLC (4 min 10-90 gradient) t _R 1.81 min; MS m / z 429.13 [M + H] ⁺ .

Example  54

3- {5-amino-4- [3- (5- methyl -[1,3,4] Oxadiazole -2 days)- Benzoyl ]- Pyrazole -1 day}- N Preparation of -cyclopropyl-4-methyl-benzamide

Prepared according to a procedure similar to that of Example 53, except that trimethylorthoacetate was used in place of trimethyl orthoformate. HPLC (4 min 10-90 gradient) t _R 1.84 min; MS m / z 443.15 [M + H] ⁺ .

Example  55

3- {5-amino-4- [3- ( Pyrrolidine -1-carbonyl)- Benzoyl ]- Imidazole -1-yl} -N- Cyclopropyl Preparation of 4-methyl-benzamide

Prepared according to a procedure analogous to that of Example 21, except that pyrrolidine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.93 min; MS m / z 458.2 [M + H] ⁺ .

Example  56

3- [5-amino-4- (3- Cyclopropylcarbamoyl - Benzoyl ) - Imidazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

Prepared according to a procedure analogous to that of Example 21, except that cyclopropylamine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.74 min; MS m / z 444.14 [M + H] ⁺ .

Example  57

3- [5-amino-4- (3- Carbamoyl - Benzoyl ) - Imidazole -1-yl] -N- Cyclopropyl -4- methyl Preparation of Benzamide

Prepared according to a procedure analogous to that of Example 21, except that ammonia was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.51 min; MS m / z 404.2 [M + H] ⁺ .

Example  58

3- [5-amino-4- (3- Isopropylcarbamoylbenzoyl ) - Pyrazole -1 day]- N - Cyclopropyl Preparation of 4-methylbenzamide

3- [5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-imidazole-4-carbonyl] -benzoic acid instead of 3- [5-amino-1- (5 Prepared according to a procedure similar to that of Example 21B, except that -cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carbonyl] -benzoic acid was used. HPLC (4 min 10-90 gradient) t _R 1.89 min; MS m / z 446.2 [M + H] ⁺ .

Example  59 to 69

The following example was prepared in a similar procedure to Example 58 except that an appropriate amine was used instead of isopropylamine.

Example  70 to 75

The following example was prepared in a similar procedure to Example 11 except that the appropriate amine was used in place of 1-methylpiperazine.

Example  76 to 93

The following example was prepared in a similar procedure to Example 17 except that the appropriate Grignard reagent was used in place of phenylmagnesium bromide.

Example  94

3- (5-amino-4- Benzoyl -2- methyl - Imidazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide  Produce

Prepared according to a procedure similar to that of Example 17, except that triethylorthoacetate was used instead of triethylorthoformate. HPLC (4 min 10-90 gradient) t _R 1.56 min; MS m / z 375 [M + H] ⁺ .

Example  95

3- (5-amino-4- Benzoyl -2-propyl- Imidazole -1-yl) -N- Cyclopropyl -4- methyl - Benzamide  Produce

Prepared according to a procedure similar to that of Example 17, except that triethylorthobutyrate was used instead of triethylorthoformate. HPLC (4 min 10-90 gradient) t _R 2.14 min; MS m / z 403 [M + H] ⁺ .

Example  96

3- [5-amino-4- (3- Carbamoylmethoxy - Benzoyl ) - Pyrazole -1 day]- N - Cyclopropyl Preparation of 4-methylbenzamide

A. {3- [5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H-pyrazole-4-car Bonil ]- Phenoxy } -Acetic acid

3- [5-amino-4- (3-hydroxy-benzoyl) -pyrazol-1-yl] -N -cyclopropyl-4-methylbenzamide (400 mg, 1.06 mmol) in DMF (20 mL) and To a stirred solution of t -butyl chloroacetate (319 mg, 2.12 mmol) was added K ₂ CO ₃ (292 Mg, 2.12 mmol) and the mixture was heated at 100 ° C overnight. The solvent was removed and the residue was suspended in EtOAc, washed with water and brine, dried over Na ₂ S0 ₄ and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc: hexane = 3: 1) to give the product (140 mg, 27%) as pale yellow oil.

B. {3- [5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H-pyrazole-4-carbonyl]- Phenoxy } -Acetic acid

The oil in the last step (180 mg, 0.37 mmol) was dissolved in DCM (5 mL), TFA (5 mL) was added and stirred at rt overnight. The volatile organics were removed, toluene was added and then removed in vacuo to yield the product (140 mg, 88%) as a white solid.

C. 3- [5-amino-4- (3- Carbamoylmethoxy - Benzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- Methylbenzamide

To a solution of the intermediate obtained in the previous step in THF (5 mL) was added SOCl ₂ (1 mL) and the mixture was stirred at rt for 2 h. The volatiles were removed and then NH ₃ (0.5 M dioxane solution) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was removed and the residue was purified by preparative TLC (EtOAc: MeOH: Et ₃ N = 100: 10: 1) followed by preparative HPLC to give the product (4.2 Mg, 10%) as a beige solid. HPLC (4 min 10-90 gradient) t _R 1.78 min; MS m / z 434.14 [M + H] ⁺ .

Example  97 to 105

The following example was prepared in a similar procedure to Example 96 except that an appropriate amine was used in place of ammonia.

Example  106

3- [5-amino-4- (3-pyrazin-2-yl- Benzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- Methylbenzamide  Produce

3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -N -cyclopropyl-4-methylbenzamide (130 mg, 0.27 mmol) in DMF (2 mL) and To a stirred solution of 2-tributylstannylpyrazine (119 mg, 0.32 mmol) was added tetrakis (triphenylphosphine) palladium (catalyst) and the mixture was heated by microwave at 160 ° C. for 15 minutes. Solvent was removed and the residue was dissolved in EtOAc. The organics were washed with water and brine and concentrated. The crude material was purified by preparative HPLC to give the desired product (6.2 mg, 5%) as a beige solid. HPLC (4 min 10-90 gradient) t _R 2.12 min; MS m / z 439.19 [M + H] ⁺ .

Example  107

3- [5-amino-4- (3-pyridin-2-yl- Benzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- Methylbenzamide  Produce

Prepared according to a procedure similar to that of Example 106, except that 2-tributylstannylpyridine was used instead of 2-tributylstannylpyrazine. HPLC (4 min 10-90 gradient) t _R 1.94 min; MS m / z 438.26 [M + H] ⁺ .

Example  108

3- [5-amino-4- (pyridine-2-carbonyl)- Pyrazole -1 day]- N - Cyclopropyl -4- methyl - Benzamide  Produce

A. 3- (5-amino-4- Cyano -Pyrazol-1-yl)- N - Cyclopropyl -4- Methylbenzamide

DIPEA (3.4 g, 26.5 mmol) was dissolved in N -cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetate (8.45 g, 26.5 mmol) and 2-ethoxymethylene malono in EtOH (100 mL). To a solution of nitrile (3.2 g, 26.5 mmol) was added and stirred at 65 ° C. for 3 hours. Solvent was removed and the residue was suspended in EtOAc (˜100 mL) and water was added to the suspension. The solid product was filtered off. The filtrate was washed with water and brine, dried over Na ₂ S0 ₄ , concentrated and purified by column chromatography on silica gel eluting with EtOAc. Filtration and chromatography gave the combined product (7.1 g, 96%) as a beige solid.

B. 3- [5-amino-4- (pyridine-2-carbonyl)- Pyrazole -1 day]- N - Cyclopropyl -4- methyl - Benzamide

Cyclohexyl magnesium chloride (5 mL, 2.0 M in Et ₂ O) was added dropwise to a solution of 2-iodopyridine (1.03 g, 5 mmol) in THF (15 mL) at −20 ° C. The mixture was stirred at this temperature for 20 minutes and then 3- (5-amino-4-cyano-pyrazol-1-yl) -N -cyclopropyl-4-methyl-benzamide (140 mg, 0.5 mmol) Was added and then stirred overnight at room temperature. The reaction was quenched by addition of an aqueous K ₂ CO ₃ solution, then the mixture was extracted with EtOAc and the organic layer was washed with water and brine. Purification by column chromatography on silica gel eluting with EtOAc gave the product (60 mg, 33%) as a white solid. HPLC (4 min 10-90 gradient) t _R 2.09 min; MS m / z 362.20 [M + H] ⁺ .

Example  108

3- (5-amino-4- Cyclopentanecarbonyl - Pyrazole -1 day)- N - Cyclopropyl -4- Methylbenzamide  Produce

3- (5-amino-4-cyano-imidazol-1-yl)-3- [5-amino-4- (3-cyano-benzoyl) instead of N -cyclopropyl-4-methyl-benzamide -Pyrazol-1-yl] -N -cyclopropyl-4-methyl-benzamide, and cyclopentylmagnesium bromide was used instead of phenyl magnesium bromide in a procedure similar to that of Example 17B. Prepared accordingly. HPLC (4 min 10-90 gradient) t _R 2.54 min; MS m / z 353.19 [M + H] ⁺ .

Example  110 to 126

The following example was prepared by a similar procedure to Example 109 except that the appropriate Grignard reagent was used in place of cyclopentylmagnesium bromide.

Example  127

3- {5-amino-4- [3-([1,3,4] Oxadiazole -2- Ylmethoxy ) - Benzoyl ]- Pyrazole -1 day}- N Preparation of -cyclopropyl-4-methylbenzamide

A. 3- [5-amino-4- (3- Hydrazinocarbonylmethoxy - Benzoyl ) - Pyrazole -1 day]- N - Cyclopropyl -4- Methylbenzamide

Compound 97A (300 mg, 0.69 mmol), t -butyl carbazate (182 mg, 1.38 mmol), EDCI (263 mg, 1.38 mmol) and HOBt (211 mg, 1.38 mmol) were added to DMF (10 mL, anhydrous). Dissolved in and stirred at room temperature for 2 hours. Solvent was removed, the residue was dissolved in EtOAc, water, K ₂ CO ₃ Washed with aqueous solution and brine and dried over Na ₂ SO ₄ . TFA / DCE (5 mL, 1: 1) was then added and stirred at room temperature for 30 minutes. The solvent was removed and the residue was dissolved in EtOAc, washed with aqueous K ₂ CO ₃ solution and dried over Na ₂ SO ₄ . The crude residue was purified by column chromatography on silica gel (EtOAc: MeOH = 10: 1) to afford the desired compound (88 mg, 28%) as a white solid.

B. 3- {5-amino-4- [3-([1,3,4] Oxadiazole -2- Ylmethoxy ) - Benzoyl ]- Pyrazole -1 day}- N - Cyclopropyl -4- Methylbenzamide

Trimethyl orthoformate (3 mL) was added to a solution of compound 52B (48 mg, 0.11 mmol) in MeOH (3 mL) and stirred at rt overnight. The solvent was removed, the solid residue was dissolved in 1,4-dioxane, 5 drops of HCl in dioxane (4 M) was added, and the mixture was heated at 120 ° C. with microwave for 30 minutes. The solvent was removed and the residue was dissolved in EtOAc and washed with water and brine. The crude product was purified by preparative HPLC to give the product (3.3 mg, 6.7%) as a white solid. HPLC (4 min 10-90 gradient) t _R 2.07 min; MS m / z 459.13 [M + H] ⁺ .

Example  128

5 -Amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H- Pyrazole -4- Carboxyl Acid (2- methyl - Cyclohexyl Preparation of Amide-amide

A. 5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H-pyrazole-4- Carboxylic acid

5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g, in water / ethanol (15 ml / 20 ml) Example 44), a solution of LiOH (1.2 g) was heated at 50 ° C. overnight. The solution was neutralized with dilute HCl (2 M), extracted with ethyl acetate (200 ml × 2) and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and ethyl acetate and diethyl ether were added. The solid produced is filtered to 5-Amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid was obtained. (0.8 g; yield: 88%).

B. 5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H-pyrazole-4- Ka Carboxylic acid (2- methyl - Cyclohexyl )-amides

5-Amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (21 mg), 2-methylcyclohexylamine (10 mg), EDCI (28 mg ) And HOBt (12 mg) were reacted in DMF (0.75 ml) for 24 hours at room temperature. Water (4 ml) was added and the solution extracted with ethyl acetate (3 mL x 2). The organic phase was then washed with water (3 mL), dried over Na ₂ S0 ₄ and evaporated. The residue was purified by a preparative TLC plate to give the desired product 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl)- Amide (19 mg, 70%) was obtained. HPLC (4 min gradient) t _R 2.34 min; MS m / z 396.31 [M + H] ⁺ .

Example  129 to 156

The following example was prepared in a similar procedure to Example 128 except that an appropriate amine was used instead of 2-methylcyclohexylamine.

Example  157

5 -Amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H- Pyrazole -4- Carboxyl Preparation of Acid (2,2-Dimethyl-propyl) -amide

Prepared according to a procedure analogous to that of Example 128, except that neopentylamine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 2.19 min; MS m / z 370.32 [M + H] ⁺ .

Example  158

5 -Amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H- Pyrazole -4- Carboxyl Acid (1-ethyl- Pyrrolidine -2- Yl methyl Preparation of Amide-amide

Prepared according to a procedure similar to that of Example 128, except that 2- (aminomethyl) -1-ethylpyrrolidine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.41 min; MS m / z 411.25 [M + H] ⁺ .

Example  159

5 -Amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H- Pyrazole -4- Carboxyl Acid (2- Pyrrolidine Preparation of -1-yl-ethyl) -amide

Prepared according to a procedure analogous to that of Example 128, except that 1- (2-aminoethyl) pyrrolidine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 1.34 min; MS m / z 397.22 [M + H] ⁺ .

Example  160

5-amino-1- (5- Cyclopropylcarbamoyl -2- methyl - Phenyl ) -1H-pyrazole-4-carboxylic acid Cyclohexyl - methyl Preparation of -amides

Prepared according to a procedure analogous to that of Example 57, except that N -methylcyclohexylamine was used instead of isopropylamine. HPLC (4 min 10-90 gradient) t _R 2.37 min; MS m / z 396.3 [M + H] ⁺ .

Example  161

3- [5-amino-4- (3- Cyanobenzoyl ) - Pyrazole -1 day] -N - Cyclopropyl -4- Methylbenzamide  Produce

A. 3- [5-amino-4- (3-iodo Benzoyl ) -Pyrazol-1-yl] -4- Methylbenzoic acid

To a stirred solution of hydrazine 2 (32.5 g, 0.160 mol, 1.0 equiv) in ethanol (3.6 L) 1 (60 g, 0.160 mol, 1.0 equiv), Preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84 )) And triethylamine (16.56 g, 0.16 mol, 1.0 equiv) were added and the mixture was heated to 65 ° C. When the temperature reached 65 ° C., all solids dissolved. After cooling, the solid was filtered to give acid 3 (22 g, 30%) as a light brown solid. HPLC (Waters x-terra 5 micron C18 column 4.6 mm × 250 mm, 1.0 mL / min, mobile phase: 0.1% TEA in H ₂ O / acetonitrile 40/60, eluted for 30 minutes) t _R 6.74 minutes, 95.2% purity.

B. 3- [5-amino-4- (3-iodo Benzoyl ) -Pyrazol-1-yl] -N- Cyclopropyl -4- methyl - Benzamide

To a stirred solution of acid 3 (21 g, 0.0469 mol, 1.0 equiv) in DMF (30 ml) was added EDCI (17 g, 0.0886 mol, 2.0 equiv), HOBt (12.6 g, 0.0939, 2.0 equiv) and diisopropylethyl Amine (24.2 g, 0.18 mol, 4.0 equiv) was added, the solution was stirred at rt for 15 min, cyclopropylamine (10.7 g, 0.0939, 2.0 equiv) was added and the reaction stirred for 1 h. The mixture was added to water, extracted with EtOAc (1 L), washed with water (2 x 200 ml) and brine (200 ml), dried over anhydrous sodium sulfate and concentrated. The product was purified by flash chromatography on silica gel eluting with 8/2 EtOAc / hexanes to give the product as a brown oil. The product was further triturated with isopropyl ether (1 L) and purified and dried under vacuum to afford amide 4 (12 g, 50%) as off-white solid.

C. 3- [5-amino-4- (3- Cyanobenzoyl ) -Pyrazol-1-yl] -N - Cyclopropyl -4- Methylbenzamide

To a stirred solution of iodide 4 (7.4 g, 0.015 mol, 1.0 equiv) in N, N-dimethyl formamide (25 ml) was added copper cyanide under N ₂ . The resulting suspension was refluxed for 1 hour. The reaction was monitored by TLC to confirm the reaction was complete. The heating was stopped and the reaction mixture was cooled down to 80 ° C. Ice reaction (15 ml), 25% aqueous ammonia (15 ml) and ethyl acetate (50 ml) were added to quench the reaction. The mixture was filtered to remove solids. An organic layer was separated from the filtrate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude material was dried under high vacuum at 60 ° C. and then purified by column using ethyl acetate as eluent to afford the product (3 g, 51%) as off white solid. HPLC (Waters X-terra 5 micron C18 column 4.6 mm × 250 mm, 1.0 mL / min, mobile phase: 0.1% TEA in H ₂ O / acetonitrile 70/30, eluted for 30 minutes) t _R 23.70 min, 99.4% purity;

Example  162

3- [5-amino-4- (3-pyrazin-2-yl- Benzoyl ) - Imidazole -1 day]- N - Cyclopropyl -4- Methylbenzamide  Produce

A. 3- [5- amino-4- (3-bromo-benzoyl) - imidazol -1-] - N - Preparation of cyclopropyl-4-methylbenzamide

To a solution of 3-bromo-1-iodobenzene (2.82 g) in THF (20 mL) was added cyclohexylmagnesium chloride (2 M in THF, 6 mL) at -40 ° C under N ₂ . The solution was kept at -40 ° C to 0 ° C for 20 minutes. Then 3- (5-amino-4-cyano-imidazol-1-yl) -N -cyclopropyl-4-methyl-benzamide (0.18 g) was added and the reaction was kept at room temperature for 1 hour. . HCl (4 M, 20 mL) was then added and the mixture was kept at room temperature for 2 days. The mixture was neutralized with K ₂ CO ₃ solution, extracted with EtOAc (2 × 100 mL), and the combined organics were dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (EtOAc) to give the desired product (0.15 g, 54%). HPLC (4 min 10-90 gradient) t _R 1.85 min; MS m / z 438.10, 441.07 [M + H] ⁺ .

B. 3- [5-amino-4- (3-pyrazin-2-yl- Benzoyl ) - Imidazole -1 day]- N - Cyclopropyl Preparation of 4-methylbenzamide

3- [5-amino-4- (3-bromobenzoyl) -imidazol-1-yl] -N -cyclopropyl-4-methylbenzamide (60 mg) in 1,4-dioxane (0.8 mL) A solution of 2-tributyltinpyrazine (120 μL) and tetrakis (triphenylphosphine) palladium (0) (30 mg) was heated at 160 ° C. for 25 minutes under microwave emission. Water (3 ml) was added and the mixture was extracted with ethyl acetate (4 mL x 2). The solvent was evaporated and purified by preparative TLC (EtOAc: MeOH = 10: 1) to afford the desired product (38 mg, 63%). HPLC (4 min 10-90 gradient) t _R 2.18 min; MS m / z 439.27 [M + H] ⁺ .

Example  163

3- [5-amino-4- (3-pyrimidin-5-yl- Benzoyl ) - Imidazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

Prepared according to a procedure similar to that of Example 162, except that 4-tributylstannylpyrimidine was used instead of 2-tributylstannylpyrazine. HPLC (4 min 10-90 gradient) t _R 1.93 min; MS m / z 439.19 [M + H] ⁺ .

Example  164

3- [5-amino-4- (3-pyrimidin-5-yl- Benzoyl ) - Imidazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

Prepared according to a procedure similar to that of Example 162, except that 2-tributylstannylpyridine was used instead of 2-tributylstannylpyrazine. HPLC (4 min 10-90 gradient) t _R 2.04 min; MS m / z 438.25 [M + H] ⁺ .

Example  165

3- [5-amino-4- (3-pyrimidin-2-yl- Benzoyl ) - Imidazole -1-yl] -N- Cyclopropyl Preparation of 4-methyl-benzamide

Prepared according to a procedure similar to that of Example 162, except that 2-tributylstannylpyrimidine was used instead of 2-tributylstannylpyrazine. HPLC (4 min 10-90 gradient) t _R 2.49 min; MS m / z 439.24 [M + H] ⁺ .

Example  166

5-amino-1- (5- Cyclopropylcarbamoyl -2- Methylphenyl )-4- Methylsulfonylbenzoyl Preparation of -1H-imidazole

A solution of 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4-methylsulfonylbenzoyl-1H-imidazole (64 mg) and oxone® (242 mg) was water / The reaction was carried out in methanol (2 ml / 2 ml) at room temperature for 2 hours. The solution was evaporated and THF / MeOH (2 ml / 2 ml) was added. The mixture was heated to dissolve the organic material and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the product (1.6 mg). HPLC (4 min 10-90 gradient) t _R 1.90 min; MS m / z 439.15 [M + H] ⁺ .

Example  167

5-amino-1- (5- Cyclopropylcarbamoyl -2- Methylphenyl ) -4- [3- (5- methyl ) Oxadiazole Preparation of 3-ylbenzoyl] -1 H-imidazole

A mixture of N -hydroxy-3-iodobenzimidine (1.31 g), acetic anhydride (1 mL) and a catalytic amount of p -toluenesulfonic acid was heated in acetic acid (10 mL) at 90 ° C. for 6 hours. The solvent was evaporated and water and methanol (1: 1; 100 mL) were added. The resulting precipitate was filtered to give the desired product (1.1 g).

To a solution of 3- (3-iodophenyl) -5-methyloxadiazole (0.286 g) in THF (15 ml) was added cyclopentylmagnesium bromide (2 M, 1.1 mL) at -20 ° C under N _2. . The temperature was gradually raised to 5-10 ° C. It took about 20 minutes. 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4-cyanoimidazole (96 mg) was then added and the reaction was maintained at room temperature for 0.5 h. Dilute HCl (4 M, 12 mL) was then added and the reaction was heated at 60 ° C. for 3 h. After partitioning between water and ethyl acetate, it was purified by final product column chromatography (ethyl acetate / hexane = 1: 1). HPLC (4 min 10-90 gradient) t _R 2.03 min; MS m / z 443.20 [M + H] ⁺ .

Example  168

3- (5-Amino-4- {3- [2- (4- methyl -piperazin-1-yl) -ethoxy ] -benzoyl } -pyrazol -1-yl) -N-cyclopropyl-4- Preparation of Methyl-benzamide

A. 3- {5-amino-4- [3- (2- Bromo - Ethoxy ) - Benzoyl ]- Pyrazole -1-yl} -N- Cyclopropyl -4-methylbenzamide

3- [5-amino-4- (3-hydroxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide in THF (anhydrous, 20 mL) (472 mg, 1.26 mmol) was added 2-bromoethanol (785 mg, 6.3 mmol), PPh ₃ (1.3 g, 5.04 mmol) and diethyl azodicarboxylate (877 mg, 5.04 mmol) at 0 ° C. and the mixture Was stirred at rt for 72 h. NH ₄ Cl aqueous solution was added, then the THF layer was isolated. The aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine and purified by preparative HPLC to give the product (360 mg, 59%) as a white solid. HPLC (4 min 10-90 gradient) t _R 2.72 min; MS m / z 483.14 / 485.09 [M + H] ⁺ .

B. 3- (4-amino-5- {3- [2- (4-methyl-piperazin-1-yl) -ethoxy] -benzoyl} - pyrazol-1-yl) -N- cyclopropyl- 4- methylbenzamide

3- {5-Amino-4- [3- (2-bromoethoxy) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide in EtOH (1 ml) (24 mg, 0.05 mmol) was added 1-methylpiperazine (100 mg, 1 mmol) and the mixture was stirred at 80 ° C. overnight. The solvent was removed and the residue was dissolved in EtOAc, washed with water and dried over Na ₂ SO ₄ . The solvent was removed and the desired product (18 mg, 72%) was obtained as a colorless oil. HPLC (4-minute gradient) t _R 1.33 min; MS m / z 503.29 [M + H] ⁺ .

Example  169

3- [5-amino-4- (3- {2- [ Vis -(2-hydroxy-ethyl) -amino]- Ethoxy } - Benzoyl ) - Pyrazole Preparation of -1-yl] -N-cyclopropyl-4-methyl-benzamide

Prepared according to a procedure similar to that of Example 168, except that 2- [bis- (2-hydroxyethyl) -amino] -ethanol was used instead of 1-methylpiperazine. HPLC (4 min 10-90 gradient) t _R 1.39 min; MS m / z 508.24 [M + H] ⁺ .

Example  170

3- {5-amino-4- [3- (2-dimethylamino- Ethoxy ) - Benzoyl ]- Pyrazole -1-yl} -N- Cyclopropyl Preparation of 4-methyl-benzamide

Prepared according to a procedure similar to that of Example 168, except that 2-dimethylaminoethanol was used instead of 1-methylpiperazine. HPLC (4 min 10-90 gradient) t _R 1.59 min; MS m / z 448.22 [M + H] ⁺ .

Example  171

Preparation of 3- {5-amino-4- [3- (2,3-dihydroxy-propoxy) -benzoyl] -pyrazol-1-yl} -N -cyclopropyl-4-methylbenzamide

A. 3- {5-amino-4- [3- (2,2-dimethyl- [1,3] Dioxolane -4- Ylmethoxy ) - Benzoyl ] -Pyrazol-1-yl} -N- Cyclopropyl -4- methyl - Benzamide

3- [5-amino-4- (3-hydroxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide (75 mg, 0.2 mmol) and 4 in DMF (4 ml) To a stirred solution of -chloromethyl-2,2-dimethyl- [1,3] dioxolane e (36 mg, 0.24 mmol) was added K ₂ CO ₃ , and the mixture was stirred in a microwave oven at 150 ° C. for 2 hours. It was. The solvent was removed and the residue was dissolved in EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (EtOAc: Hex = 3: 1) to give the product (18 mg, 18%) as a colorless oil. HPLC (4 min gradient) t _R 2.57 min; MS m / z 491.11 [M + H] ⁺ .

B. 3- {5-Amino-4- [3- (2,3-dihydroxy-propoxy) -benzoyl] -pyrazol-1-yl} -N -cyclopropyl-4-methylbenzamide

Compound 171A (10 mg) was dissolved in HOAc (1 ml), 0.5 ml of water was added and the mixture was stirred at 50 ° C. overnight. The solvent was removed and the residue was purified by preparative TLC (EtOAc) to give the product (4.1 mg, 45%) as pale yellow oil. HPLC (4 min 10-90 gradient) t _R 1.73 min; MS m / z 451.21 [M + H] ⁺ .

Example  172

3- (5-amino-4- {3- [2- (4- Chloro - Phenoxy ) - Ethoxy ]- Benzoyl } - Pyrazole -1-yl) -N- Cyclopropyl Preparation of 4-methyl-benzamide

3- {5-amino-4- [3- (2-bromoethoxy) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide (24 in DMF (1 mL) mg, 0.05 mmol) and 4-chlorophenol (128 mg, 1 mmol) were added K ₂ CO ₃ (138 mg, 1 mmol) and the mixture was stirred at 100 ° C for 2 h. The mixture was cooled and the solid was filtered off. The filtrate was concentrated and purified by preparative HPLC to give the product (10 mg, 38%) as a beige solid. HPLC (4 min 10-90 gradient) t _R 2.77 min; MS m / z 531.21 [M + H] ⁺ .

Example  173

3- {5-amino-4- [3- (4H- [1,2,4] Triazole -3 days)- Benzoyl ]- Pyrazole -1-yl} -N- Cyclopropyl Preparation of 4-methyl-benzamide

Stirred of 3- [5-amino-4- (3-carbamoyl-benzoyl) -pyrazol-1-yl] -N -cyclopropyl-4-methylbenzamide (120 mg) in DMF (2 mL) To the solution was added N-dimethylformamide dimethyl acetal (5 ml) and the solution was stirred at 80 ° C overnight. The solvent was removed, the residue was dissolved in AcOH (5 ml), hydrazine monohydrate (3 ml) was added and the mixture was stirred at 90 ° C. overnight. The solution was acidified to pH ˜1 with hydrochloric acid and stirred at 80 ° C. overnight. The solvent was removed and the residue was resuspended in EtOAc, then washed with aqueous K ₂ CO ₃ aqueous solution, water and brine and concentrated. The crude product was purified by column chromatography on silica gel eluting with EtOAc to give the product (65 mg, 51%) as a white solid. HPLC (4 min 10-90 gradient) t _R 1.58 min; MS m / z 428.18 [M + H] ⁺ .

Example  174

3- {5-amino-4- [3- (4H- [1,2,4] Triazole -3 days)- Benzoyl ]- Pyrazole -1-yl} -N- Cicle Preparation of Ropropyl-4-methyl-benzamide

3- [5-amino-4- (3-carbamoyl-benzoyl) -pyrazol-1-yl]-3- [5-amino-4- (3 instead of N -cyclopropyl-4-methylbenzamide Prepared according to a procedure analogous to that of Example 173, except that -carbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide was used. HPLC (4 min 10-90 gradient) t _R 1.58 min; MS m / z 428.24 [M + H] ⁺ .

Example  175

The following in vitro assays could be used to demonstrate that the compounds provided herein can inhibit the synthesis or activity of cytokines.

p38 Kinase  produce

The cDNAs of human p38α and β were cloned by PCR. α and β cDNAs were subcloned into the DEST2 plasmid (InVitrogen, Gateway). His _6- p38 fusion protein. It was expressed in E. coli and purified from bacterial lysates by affinity chromatography using Ni ⁺² -NTA-agarose. His _6- p38 protein was activated by incubation with essentially active MKK6. Active p38 was isolated from MKK6 by affinity chromatography. Essentially active MKK6 is described by Raingeaud et al. , Mol . Cell. Biol ., 1247-1255 (1996).

LPS -stimulus PBMC On by TNF -α generation

Heparinized human whole blood was obtained from healthy volunteers. Peripheral blood mononuclear cells (PBMCs) were purified from human whole blood by Accu-paque density gradient centrifugation and assay media (RPM with 10% fetal bovine serum) at a concentration of 5 × 10 ⁶ cells / ml. Resuspended in the medium). 175 μL of cell suspension was incubated for 30 minutes at room temperature with 10 μL of test compound (in 4% DMSO) in 96-well tissue culture plates. 15 μL of LPS (13.33 μg / ml stock) was then added to the cell suspension and the plates were incubated for 18 hours at 37 ° C. under a humidified atmosphere containing 5% CO ₂ . After incubation, cell culture medium was collected and stored at -20 ° C.

THP-1 cells (TIB-202, ATCC) were washed and resuspended in assay medium (RPMI medium containing 3% fetal bovine serum) at a concentration of 1 × 10 ⁵ cells / ml. 175 μL of cell suspension was incubated for 30 minutes at room temperature with 10 μL of test compound (in 4% DMSO) in 96-well tissue culture plates. 15 μL of LPS (13.33 μg / ml stock) was then added to the cell suspension and the plates were incubated for 18 hours at 37 ° C. under a humidified atmosphere containing 5% CO ₂ . After incubation, cell culture medium was collected and stored at -20 ° C.

TNF-α concentration in the medium was quantified using a standard ELISA kit (BioSource International, Camarillo, CA.) The concentration of TNF-α and the IC ₅₀ value of the test compound (LPS-stimulated TNF production) The concentration of compound that inhibits up to 50%) was calculated by a four-parameter logistic curve (SigmaPlot, SPSS, Inc.).

p38 α analysis

The p38α assay used is based on the determination of ADP released in the reaction of interest via NADH oxidation obtained by coupling with pyruvate kinase and lactate dehydrogenase reactions. Assays were performed in 384-well UV plates. The final dose was 25 μL prepared by adding 2.5 μL compound dissolved in 10% DMSO, 17.5 μL assay buffer and 5 μL ATP. Assay buffer contains the following reagents to provide the final concentration in the assay: 25 mM HEPES, 20 mM 2-glycerophosphate, pH 7.6, 10 mM MgCl ₂ , 0.1 mM sodium orthovanadate, 0.5 mM phosphoenol Pyruvate, 0.12 mM NADH, 3.1 mg / ml LDH, 6.67 mg / ml pyruvate kinase, 0.25 mM peptide substrate, 2 mM DTT, 0.005% Tween 80 and 20 nM p38α kinase from Upstate. The test compound was preincubated with p38α kinase for 60 minutes and the reaction was initiated by adding ATP to a final concentration of 0.15 mM. The reaction rate was measured at 37 ° C. for 10 minutes using a SpectraMax plate read spectrometer at 340 nm. Sigma plots were used to analyze inhibition data by nonlinear least squares regression.

LPS By stimulating mice TNF -α generation

Mice (Balb / c female, 6-8 weeks old, Taconic Labs; n = 8 / treated group) lipopolysaccharide (LPS) suspended in sterile saline (E. coli strain 0111: B4 kg per kg) 50 μg, Sigma) was injected intraperitoneally. After 90 minutes, mice were sedated by CO ₂ : O ₂ inhalation and blood samples were obtained. Serum was isolated and analyzed for TNF-α concentration by commercial ELISA assay according to the manufacturer's instructions (BioSource International). Test compounds were orally administered at various times followed by injection of LPS. The compounds were administered in suspension or solution in various vehicles or solubilizers.

result

All of the compounds exemplified herein showed activity in this assay as p38 kinase inhibitors. The p38 inhibitory activity of certain compounds provided herein is shown in the table below. p38 kinase IC ₅₀ In the value, "+++" represents less than 1 μM, "++" represents 1.0 to 10 μM and "+" represents more than 10 μM.

Since modifications will be apparent to those skilled in the art, it is to be understood that the subject matter claimed is limited only by the appended claims.

Claims (129)

A compound of the formula: or a pharmaceutically acceptable salt thereof.

In the formula, R ¹ is hydrogen; R ² is hydrogen, alkyl, alkylthio, alkylsulfonyl, alkoxy which may be substituted, where up to two substituents are selected from -OR (R = alkyl) and phenyl, 3-chlorobenzylaminocarbonylmethoxy or Heterocyclyloxy which may be substituted, wherein heterocyclyl means a cyclic non-aromatic radical of 3 to 8 ring atoms, wherein one or two ring atoms are N, the other ring atom is C, 2 Or fewer substituents are -COOR (R is selected from alkyl); G is phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl, substituted with R ³ and R ⁴ , provided that the pyridyl ring is bonded to a carbonyl group via a carbon ring atom, or G is OR ⁸³ or NR ⁸⁰ R ⁸¹ ego; B is phenyl; C is a pyrazole or imidazole ring; D contains 1 to 3 N heteroatoms and the other ring atom is heteroaryl which means a monovalent monocyclic radical of 5 to 10 ring atoms which is C or —CO (O) NR ^80x R ^81x (where , R ^80x and R ^81x are hydrogen, alkoxy or cycloalkyl containing one ring and 3 to 7 carbon atoms), Each R ⁸⁰ and R ⁸¹ is independently hydrogen, alkyl or cycloalkyl (having from 1 to 3 rings, having from 3 to 7 carbon atoms per ring, and further fused with unsaturated C ₃ -C ₇ carbocyclic rings Saturated non-aromatic cyclic hydrocarbon system, which may be unsubstituted or substituted with alkyl, 1-ethynylcyclohexyl, methoxybenzyl, benzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, cyclohexylmethyl, 3,4- Dichlorobenzyl, 3-trifluoromethylbenzyl, fluorobenzyl, N-ethyl-2-pyridinylmethyl, methylbenzyl, pyridylmethyl, morpholinylethyl, 1-cyclohexylethyl, 1-phenylethyl or 2- Substituted with 1 or 2 substituents independently selected from pyridinylethyl; R ⁸³ is hydrogen, alkyl or cycloalkyl which is a saturated non-aromatic hydrocarbon ring having 3 to 7 carbon atoms; R ³ is (a) amino, alkylamino or dialkylamino; (b) optionally substituted heterocyclyl (where one or two ring atoms are heteroatoms selected from N and O, the other ring atoms are C, and the substituents can be one or two independently selected alkyl substituents) , A cyclic nonaromatic radical of 3 to 8 ring atoms; (c) heteroaryl which may be substituted (5 to 10, wherein 1 to 3 ring atoms are selected from N and O, the other ring atom is C, and the substituent may be one or two independently selected alkyl substituents) Monocyclic radicals of two ring atoms; (d) heterocyclylalkyl which may be substituted, wherein heterocyclyl is a heteroatom in which one or two ring atoms are selected from N and O, another ring atom is C and the substituents are two independently selected Cyclic non-aromatic radical of 3 to 8 ring atoms, which may be a substituent; (e) morpholino-, piperidino-, pyrrolidino- or S, S-dioxothiomorpholino-alkoxy which may be substituted by alkyl; (f) -Y- (alkylene) -R ⁹ , wherein Y is -O-; R ⁹ has 1 to 3 ring heteroatoms selected from N and O, and other ring atoms are C, -COOH, -COR ¹⁰ Or -CONR ¹² R ¹³ , R ¹⁰ is alkyl and R ¹² and R ¹³ are independently heteroaryl which is a monocyclic aromatic radical of 5 to 10 ring atoms, independently of one another hydrogen or alkyl; (g) -CONR ²⁵ R ²⁶ wherein R ²⁵ and R ²⁶ independently represent hydrogen or alkyl, or R ²⁵ and R ²⁶ together with the nitrogen to which they are attached pyrrolidino, piperidino, morpholino, Piperazino or S, S-dioxothiomorpholino); (h) hydrogen; (i) halo; (j) cyano; (k) hydroxy; (l) phenyl, -CONR'R ", wherein R 'and R" together form pyrrolidino or morpholino, NRR', wherein R and R 'are independently selected from hydrogen and alkyl, And alkoxy, which may be substituted with one or two substituents selected from -OR where R is hydrogen or alkyl; (m) C (L) R ⁴⁰ where L is O and R ⁴⁰ is hydrogen, OR ⁵⁵ or NR ⁵⁷ R ⁵⁸ ; wherein R ⁵⁵ is hydrogen or alkyl, alkenyl, alkynyl, aryl, heteroaryl, hetero Arylene, cycloalkyl or heterocyclyl; R ⁵⁷ and R ⁵⁸ are each independently hydrogen or cycloalkyl containing one ring and 3 to 7 carbon atoms), (n) alkyl or hydroxyalkyl; (o) 2- (4-methylpiperazin-1-yl) -2-exo-ethoxy, 2- (3-amino-pyrrolidin-1-yl) -2-oxo-ethoxy, 2- ( 3-Methylamino-pyrrolidin-1-yl) -2-oxo-ethoxy, [(1H-benzoimidazol-2-ylmethyl) -carbamoyl] -methoxy, [2- (2-benzyl Oxy-5-chloro-phenyl) -ethylcarbamoyl] -methoxy, [2- (5-chloro-2-hydroxy-phenyl) -ethylcarbamoyl] -methoxy or 4-piperazinylmethyl; (p) cyclopropoxy; (q) methylthio; And (r) methylsulfonyl Is selected from the group consisting of R ⁴ is (a) hydrogen; (b) halo; (c) alkyl; (d) alkoxy; And (e) hydroxy Selected from the group consisting of; Or R ³ and R ⁴ substitute for adjacent atoms on the ring to form an alkylenedioxy; R ⁵ is hydrogen; R ⁶ is (a) hydrogen; And (b) alkyl Selected from the group consisting of; 3- (5-Amino-4- {3-[(3-chloro-benzylamino) -methyl] -benzoyl} -pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide, 3- [5-Amino-4- (3-{[2- (3-chloro-phenyl) -ethylamino] -methyl} -benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benz Amide, 3- (5-amino-4- {3- [4- (3-chloro-phenyl) -piperazin-1-ylmethyl] -benzoyl} -pyrazol-1-yl) -N-cyclopropyl- 4-Methyl-benzamide, 3- [5-amino-4- (3-{[2- (2-benzyloxy-5-chloro-phenyl) -ethylamino] -methyl} -benzoyl) -pyrazole-1 -Yl] -N-cyclopropyl-4-methyl-benzamide, 3- (5-amino-4- {3-[(2-morpholin-4-yl-ethylamino) -methyl] -benzoyl} -pyra Zol-1-yl) -N-cyclopropyl-4-methyl-benzamide, 3- (5-amino-4- {3-[(3-morpholin-4-yl-propylamino) -methyl] -benzoyl } -Pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide, 3- [5-amino-4- (3-vinyloxy-benzoyl) -pyrazol-1-yl] -N- Cyclopropyl-4-methyl-benzamide, 5-amino-1- (5- Clopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid phenylamide, 3- {5-amino-4- [3- (4H- [1,2,4] triazole -3-yl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide or 3- (5-amino-4- {3- [2- (3,5-dimethyl -Piperazin-1-yl) -2-oxo-ethoxy] -benzoyl} -pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide, Wherein alkyl and alkoxy are linear saturated monovalent hydrocarbon radicals of 1 to 6 carbon atoms or branched saturated monovalent hydrocarbons of 3 to 6 carbon atoms. The compound of claim 1, wherein G is OR ⁸³ or NR ⁸⁰ R ⁸¹ . The compound of claim 1, wherein G is phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl and substituted with R ³ and R ⁴ . The compound of claim 1, wherein G is phenyl and substituted with R ³ and R ⁴ . The compound of claim 1, wherein C is an imidazole ring. The compound of claim 1, wherein C is a pyrazole ring. A compound according to claim 1 which is a compound of formula III or a pharmaceutically acceptable salt thereof. <Formula III>

Where A corresponds to G and is phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl. The compound of claim 1 which is a compound of formula VII or a pharmaceutically acceptable salt thereof. <Formula VII>

Where A corresponds to G and is phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl. The compound of claim 1, wherein R ¹ is hydrogen. The compound of claim 1, wherein R ² is hydrogen, methyl, n-propyl or 3-chlorobenzylaminocarbonylmethoxy. 8. A compound according to claim 7, wherein A is a phenyl ring. 8. A compound according to claim 7, wherein B is a phenyl ring. The compound of claim 1, wherein R ³ is cyano. The compound of claim 1, wherein R ³ is hydrogen, independently dioxolanyl, pyrimidinyl, pyridyl, pyrazinyl, cyano, oxadizolyl, which may be substituted with one or two C _1-6 alkyl substituents, Triazolyl, methylthio or methanesulfonyl. The compound of claim 1, wherein R ³ is N -morpholinylmethyl, hydroxymethyl, N- (2- (3-chlorophenyl) -1-ethyl) aminomethyl, N- (2-morpholinyl-1- Ethyl) aminomethyl, (3-chloro-benzylamino) -methyl, 4- (3-chloro-phenyl) -piperazin-1-ylmethyl, [2- (2-benzyloxy-5-chloro-phenyl)- Ethylamino] -methyl, (3-morpholin-4-yl-propylamino) -methyl, carbamoylmethoxy, 2- (4-methyl-piperazin-1-yl) -2-oxo-ethoxy, 2-oxo-2-piperazin-1-yl-ethoxy, 2- (3-amino-pyrrolidin-1-yl) -2-oxo-ethoxy, 2- (3-methylamino-pyrrolidine -1-yl) -2-oxo-ethoxy, 2- (3,5-dimethyl-piperazin-1-yl) -2-oxo-ethoxy, 2-morpholin-4-yl-2-oxo- Ethoxy, [(1H-benzoimidazol-2-ylmethyl) -carbamoyl] -methoxy, [2- (2-benzyloxy-5-chloro-phenyl) -ethylcarbamoyl] -methoxy, [2- (5-Chloro-2-hydroxy-phenyl) -ethylcarbamoyl] -methoxy or 4-piperidinylmethyl. 8. The compound of claim 7, wherein R ⁴ is hydrogen. 8. The compound of claim 7, wherein R ⁵ is methyl. 8. The compound of claim 7, wherein R ⁶ is hydrogen. The compound of claim 1, wherein R ¹ and R ² are hydrogen and B is phenyl. The compound of claim 1, wherein R ³ is present at the 3-position. The method of claim 1, 3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -N-methoxy-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-pyrazol-1-yl) -N-methoxy-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-pyrazol-1-yl) -4-methyl-benzoic acid; 3- (5-Amino-4-benzoyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -4-methyl-benzoic acid; 3- [5-amino-4- (3-iodo-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; {5-Amino-1- [2-methyl-5- (4H- [1,2,4] triazol-3-yl) -phenyl] -1 H-pyrazol-4-yl} -phenyl-methanone; 3- [5-amino-4- (3- [1,3] dioxolan-2-yl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-formyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-hydroxymethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (4-methyl-piperazin-1-ylmethyl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-morpholin-4-ylmethyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (2-morpholin-4-yl-ethoxy) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-benzyloxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-hydroxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-methyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; And 3- (5-Amino-4-benzoyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide. The compound of claim 1, which is 3- (5-amino-4-benzoyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide or a pharmaceutically acceptable salt thereof. The method of claim 1, 3- (5-Amino-4-benzoyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4-cyclohexanecarbonyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4-cyclopentanecarbonyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4-phenylacetyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-isopropylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (2-dimethylamino-ethylcarbamoyl) -benzoyl] -imidazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-ethylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-methylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-cyclopropylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-cyclopentylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (morpholin-4-carbonyl) -benzoyl] -imidazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (cyclopropylmethyl-carbamoyl) -benzoyl] -imidazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (tetrahydro-pyran-4-carbonyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-3-methoxy-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-3-ethoxy-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4-benzoyl-3- (2-methoxy-ethoxy) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4-benzoyl-3- (2-benzyloxy-ethoxy) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 4- [5-Amino-4-benzoyl-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazol-3-yloxy] -piperidine-1-carboxylic acid tert Butyl ester; 3- [5-amino-4-benzoyl-3- (piperidin-4-yloxy) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-3-methanesulfonyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methanesulfonyl-1H-pyrazole-4-carboxylic acid amide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester; 3- [5-amino-4- (3-chlorobenzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-methyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- [5-amino-4- (2-methylbenzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (2-methoxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-chlorobenzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (2-chlorobenzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-methoxy-benzoyl) -pyrazol-1-yl] -4, N-dimethyl-benzamide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester; 5-Amino-3-[(3-chloro-benzylcarbamoyl) -methoxy] -1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid Ethyl esters; 3- (5-Amino-4-benzoyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-cyanobenzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- [5-amino-4- (3- [1,3,4] oxadiazol-2-yl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- {5-Amino-4- [3- (5-methyl- [1,3,4] oxadiazol-2-yl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4 -Methyl-benzamide; 3- {5-Amino-4- [3- (pyrrolidine-1-carbonyl) -benzoyl] -imidazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-cyclopropylcarbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-carbamoyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-isopropylcarbamoylbenzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- [5-amino-4- (4-methylcarbamoyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (4-cyclopropylcarbamoyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-carbamoyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (piperazin-1-carbonyl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-dimethylcarbamoyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (cyclopropylmethyl-carbamoyl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-ethylcarbamoyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-methylcarbamoyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-cyclopentylcarbamoyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-isopropylcarbamoyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-cyclopropylcarbamoyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4- {3-[(3-chloro-benzylamino) -methyl] -benzoyl} -pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-{[2- (3-chloro-phenyl) -ethylamino] -methyl} -benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl Benzamide; 3- (5-Amino-4- {3- [4- (3-chloro-phenyl) -piperazin-1-ylmethyl] -benzoyl} -pyrazol-1-yl) -N-cyclopropyl-4- Methyl-benzamide; 3- [5-Amino-4- (3-{[2- (2-benzyloxy-5-chloro-phenyl) -ethylamino] -methyl} -benzoyl) -pyrazol-1-yl] -N-cyclo Propyl-4-methyl-benzamide; 3- (5-Amino-4- {3-[(2-morpholin-4-yl-ethylamino) -methyl] -benzoyl} -pyrazol-1-yl) -N-cyclopropyl-4-methyl- Benzamide; 3- (5-Amino-4- {3-[(3-morpholin-4-yl-propylamino) -methyl] -benzoyl} -pyrazol-1-yl) -N-cyclopropyl-4-methyl- Benzamide; 3- [5-amino-4- (pyridine-2-carbonyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (2-methyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3,4-difluoro-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-fluoro-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3,4-dichloro-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-methoxy-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-fluoro-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3,5-dichloro-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-methoxy-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-imidazole-4-carbonyl] -benzoic acid tert-butyl ester; 3- [5-amino-4- (3,5-difluoro-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (benzo [1,3] dioxol-5-carbonyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-chloro-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3,4-dimethoxy-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-benzyloxy-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-fluoro-3-methyl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide; {3- [5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-imidazole-4-carbonyl] -phenoxy} -acetic acid tert-butyl ester; 3- [5-amino-4- (3-chloro-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4-benzoyl-2-methyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide: 3- (5-Amino-4-benzoyl-2-propyl-imidazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-carbamoylmethoxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- (5-Amino-4- {3- [2- (4-methyl-piperazin-1-yl) -2-oxo-ethoxy] -benzoyl} -pyrazol-1-yl) -N-cyclo Propyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (2-oxo-2-piperazin-1-yl-ethoxy) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl- Benzamide; 3- (5-amino-4- {3- [2- (3-amino-pyrrolidin-1-yl) -2-oxo-ethoxy] -benzoyl} -pyrazol-1-yl) -N- Cyclopropyl-4-methyl-benzamide; 3- (5-amino-4- {3- [2- (3-methylamino-pyrrolidin-1-yl) -2-oxo-ethoxy] -benzoyl} -pyrazol-1-yl) -N -Cyclopropyl-4-methyl-benzamide; 3- (5-amino-4- {3- [2- (3,5-dimethyl-piperazin-1-yl) -2-oxo-ethoxy] -benzoyl} -pyrazol-1-yl) -N -Cyclopropyl-4-methyl-benzamide; 3- {5-Amino-4- [3- (2-morpholin-4-yl-2-oxo-ethoxy) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl- Benzamide; 3- [5-Amino-4- (3-{[(1H-benzoimidazol-2-ylmethyl) -carbamoyl] -methoxy} -benzoyl) -pyrazol-1-yl] -N-cyclo Propyl-4-methyl-benzamide; 3- [5-Amino-4- (3-{[2- (2-benzyloxy-5-chloro-phenyl) -ethylcarbamoyl] -methoxy} -benzoyl) -pyrazol-1-yl]- N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-{[2- (5-chloro-2-hydroxy-phenyl) -ethylcarbamoyl] -methoxy} -benzoyl) -pyrazol-1-yl]- N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-pyrazin-2-yl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- [5-amino-4- (3-pyridin-2-yl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- [5-amino-4- (pyridine-2-carbonyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- (5-amino-4-cyclopentanecarbonyl-pyrazol-1-yl) -N-cyclopropyl-4-methylbenzamide; 3- [5-amino-4- (benzo [1,3] dioxol-5-carbonyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- [5-amino-4- (2-fluoro-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-ethoxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-methoxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-Amino-4- (3-cyclopropoxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-methoxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3,4-dimethoxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-methylsulfanyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-methylsulfanyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-fluoro-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-fluoro-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3,4-difluoro-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3,5-difluoro-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-fluoro-3-methyl-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (4-fluoro-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- (5-Amino-4-cyclohexanecarbonyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-vinyloxy-benzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- {5-amino-4- [3-([1,3,4] oxadiazol-2-ylmethoxy) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methylbenz amides; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (2-methyl-cyclohexyl) -amide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid phenylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (1-ethyl-propyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid bicyclo [2.2.1] hept-2-ylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (1-ethynyl-cyclohexyl) amide; 3- [5-amino-4- (2,5-dimethyl-pyrrolidine-1-carbonyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid 4-methoxy-benzylamide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid indan-1-ylamide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid benzylamide; 3- [5-amino-4- (piperidin-1-carbonyl) -pyrazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid cyclohexylamide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1H-pyrazole-4-carboxylic acid cyclopropylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid 3-chlorobenzylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid cyclopentylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid 2,4-dichloro-benzylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid cyclohexylmethyl-amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid 3,4-dichloro-benzylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (4-methyl-cyclohexyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (4-tert-butyl-cyclohexyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (2,2-dimethyl-propyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid 3-methoxy-benzylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid 4-fluoro-benzylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (1-ethyl-pyrrolidin-2-ylmethyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid 2-methyl-benzylamide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (pyridin-2-ylmethyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (1-cyclohexyl-ethyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (1-phenyl-ethyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (2,2-dimethyl-propyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (1-ethyl-pyrrolidin-2-ylmethyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid (2-pyrrolidin-1-yl-ethyl) -amide; 5-Amino-1- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 3- [5-amino-4- (3-cyanobenzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- [5-amino-4- (3-pyrazin-2-yl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methylbenzamide; 3- [5-amino-4- (3-pyrimidin-5-yl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-pyrimidin-5-yl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 3- [5-amino-4- (3-pyrimidin-2-yl-benzoyl) -imidazol-1-yl] -N-cyclopropyl-4-methyl-benzamide; 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4-methylsulfonylbenzoyl-1H-imidazole; 5-amino-1- (5-cyclopropylcarbamoyl-2-methylphenyl) -4- [3- (5-methyl) oxadiazol-3-ylbenzoyl] -1 H-imidazole; 3- (5-Amino-4- {3- [2- (4-methyl-piperazin-1-yl) -ethoxy] -benzoyl} -pyrazol-1-yl) -N-cyclopropyl-4- Methyl-benzamide; 3- [5-Amino-4- (3- {2- [bis- (2-hydroxy-ethyl) -amino] -ethoxy} -benzoyl) -pyrazol-1-yl] -N-cyclopropyl- 4-methyl-benzamide; 3- {5-Amino-4- [3- (2-dimethylamino-ethoxy) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl-benzamide; 3- {5-amino-4- [3- (2,3-dihydroxy-propoxy) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methylbenzamide; 3- (5-Amino-4- {3- [2- (4-chloro-phenoxy) -ethoxy] -benzoyl} -pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide ; 3- {5-Amino-4- [3- (4H- [1,2,4] triazol-3-yl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl- Benzamide; 3- {5-Amino-4- [3- (4H- [1,2,4] triazol-3-yl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl- Benzamide; And 3- {5-Amino-4- [3- (4H- [1,2,4] triazol-3-yl) -benzoyl] -pyrazol-1-yl} -N-cyclopropyl-4-methyl- Benzamide; Or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 3- [5-amino-4- (3-cyanobenzoyl) -pyrazol-1-yl] -N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is 3- (5-amino-4-benzoyl-pyrazol-1-yl) -N-cyclopropyl-4-methyl-benzamide. The compound of claim 22 in the form of a pharmaceutically acceptable salt. The compound of claim 24 in the form of a pharmaceutically acceptable salt. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete